Open access peer-reviewed chapter

IFN-γ versus IL-17: A Battle During Cardiac Autoimmunity Evolution

Written By

Eleonora Kurtenbach and Camila Guerra Martinez

Submitted: 27 April 2016 Reviewed: 18 November 2016 Published: 22 March 2017

DOI: 10.5772/66986

From the Edited Volume

Immunopathogenesis and Immune-based Therapy for Selected Autoimmune Disorders

Edited by Mourad Aribi

Chapter metrics overview

1,680 Chapter Downloads

View Full Metrics


Cardiovascular diseases are the leading global cause of death. Cardiomyopathies are the most prevalent forms of heart failure diseases currently. They may have genetic or environmental etiology, and the development of an autoimmune process is essential for the progression of the disease. During an autoimmune response, there is the breakdown of self-tolerance and generation of a T-lymphocytes-mediated cellular autoimmune response and B-lymphocytes-mediated humoral autoimmune response. Lymphocytes perpetuate the autoimmune response throughout the release of cytokines, expansion of autoreactive clones, and attenuation of regulatory mechanisms. Increasing evidences indicate that interferon (IFN)-γ and interleukin (IL)-17 participate during autoimmune disorders development. The use of autoimmune cardiomyopathy models revealed antagonistic functions for both cytokines during the evolution of autoimmune cardiomyopathy: while enhanced IFN-γ levels are associated to a lower disease severity, the levels of IL-17 are inversely correlated to a favorable prognosis. More precisely, recent findings indicate that the IFN-γ/IL-17 ratio in combination with other cytokine levels dictates heart’s autoimmunity development and dilatation. In this chapter, we discuss the role played by the autoimmune response in the development of cardiomyopathy. We also discuss some immune mechanisms focused on IFN-γ and IL-17’s ability to induce and perpetuate cardiac autoimmunity.


  • autoimmunity
  • cardiomyopathy
  • IL-17
  • IFN-γ and immunological response

1. Introduction

Cardiovascular diseases are responsible for over 17 million deaths per year worldwide, representing the leading cause of deaths globally (WHO 2015— Among the main disorders that directly affect the heart and/or circulatory system, there are the coronary heart diseases, cerebrovascular accident, hypertension, peripheral arterial diseases, congenital heart diseases, and heart failure [1]. Currently, cardiomyopathies are the most prevalent form of heart failure [2].

About 30% of cardiomyopathies have genetic origins, most of them are autosomal dominant, but there are also cases of X-linked-recessive inheritance and even mitochondrial DNA mutations. In 2015, more than 110 nuclear and 24 mitochondrial genes were correlated with cardiomyopathies [35]. Cardiomyopathy patients showed enhanced expression of the mutated genes TTN (titin, 27%), LLMNA (laminin A/C, 6%), MYBPC (myosin-binding protein C, 3%), TNNT2 (cardiac troponin C, 3%), MYH6 (myosin heavy chain 6, 3%), and SCN5A (sodium channel voltage-dependent-α5, 3%) [68]. In addition to the classic cases of sarcomeric protein mutations, an association between single nucleotide polymorphisms (SNPs) and predisposition to cardiomyopathies in some specific populations has also been reported. These SNPs were mainly observed in genes related to the immune response, such as CTLA-4 (cytotoxic T-lymphocyte antigen-4), IL-6 (interleukin-6), TNF-α (tumor necrosis factor alpha), and HLA (human leukocyte antigen) [9, 10].

Cardiomyopathy can also be induced by excessive alcohol consumption, poisoning by heavy metals or medications (e.g., doxorubicin), metabolic abnormalities, and microbial infections (Figure 1) [11]. Among the non-infectious etiologies, alcohol consumption is probably the main cause of cardiomyopathy in the Occidental world [10, 12, 13]. Viral infections are the most common form of microbial-mediated cardiomyopathy in Europe and North America [14]. Analysis of patient biopsies revealed that coxsackie B3 virus infection is the leading cause of cardiomyopathy, followed by parvovirus B19, enterovirus, adenovirus, human herpes virus 6, and HIV infection [15, 16].

Figure 1.

Proposed mechanisms in the development of cardiac autoimmunity. Infection caused by virus, bacteria, protozoa, and other stimuli (A) are recognized by receptors of the innate response, such as TLR and NLRs, leading to cardiomyocytes damage and death. During this process, the assembly of a multiprotein complex known as inflammasome may occur, responsible for secretion of cytokines and the amplification of an autoimmunity cascade. Also, diseases as diabetes and hypertension may activate oxidative and mechanical stress responses, respectively (B and C). These can lead to a redox imbalance and a change in protein processing, amplifying the heart damage. Proteins from infectious agents may exhibit similarity with host proteins, a process known as molecular mimicry (D). All these processes jointly or separately will provoke the exposure of cardiac antigens via MHC I by cardiomyocytes or via MHC II by antigen-presenting cells (APCs) after cardiac antigens or apoptotic cardiomyocytes phagocytosis. These processes will stimulate B-cells, CD4+ and CD8+ T-cells to mount humoral and cellular autoimmune responses. Besides, cardiac antigens can stimulate additional damages via TLR activation (E), as positive feedback. Gray continuous arrows represent mechanisms described in this review while gray dashed arrows not.

In Latin America, Chagas´ cardiomyopathy is one of the most common forms of morbidity and mortality in Trypanosoma cruzi-infected people, now estimated in the order of 5.7 million people. Approximately one-third of these patients will develop a dilated chronic form of heart failure associated to a worst clinical prognosis [16, 17]

During the development of cardiomyopathy, these genetic or environmental conditions are considered initiators that cause local damage. The disease progression will activate immune response mechanisms, which may lead to the clearance of the infectious agent and/or the defective cardiomyocytes. However, this initial trigger can also activate an immune status that modulates disease progression to a chronic state of cardiomyopathy (Figure 1). The literature suggests that the development of autoimmune processes is the key element in the progression of cardiomyopathy regardless of its etiological origin [11, 18]. Nonetheless, the specific role of the complex immune system response in the induction of cardiac autoimmunity and perpetuation of cardiomyopathy is poorly understood. Recent findings that shed some light in the immune mechanisms of cardiomyopathy induction will be described below.


2. Development of cardiac autoimmunity

Cardiomyocyte cellular damage may be induced by infection with pathogens, endogenous stress from mechanical or oxidative traumas, or from mutated proteins (Figure 1AC) [1922]. These insults promote activation of the innate immune response through pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and Nod-like receptors (NLRs). PRRs are expressed in immune cells, such as macrophages, dendritic cells and lymphocytes, cardiac fibroblasts, and cardiomyocytes (Figure 1) [2326]. Activation of heart receptors such as TLR2, TLR4, and TLR5 induces the expression of IL-6, MIP-2 (macrophage inflammatory protein 2), KC (CXCL 1 – homolog of human IL-8), and ICAM-1 (intercellular adhesion molecule-1), and is associated with a decrease in cardiomyocyte contractility [26, 27]. The absence of host immunity receptors or associated pathway components inhibits the development of cardiomyopathies, as observed using an autoimmune animal model in mice depleted for TLR-7−/−, TLR-9−/−, and MyD88−/− [28].

The listed factors may cause a chronic condition and lead to the activation of cell death mechanisms by apoptosis or necrosis [2931]. Apoptotic cardiomyocytes are processed by antigen-presenting cells, such as dendritic cells and macrophages, resulting in immune system activation, myocarditis, and production of autoantibodies against heart protein, as anti-myosin antibodies [32, 33]. The death of cardiomyocytes releases autoantigens which are captured by dendritic cells and leads to a "self-aggressive" state through the activation of CD40 and TLR receptors. This dendritic cell-mediated activation mechanism is an important regulator of CD4+ T-cell function [32, 34]. The endocytosed cardiac antigens will be processed and coupled to a molecule of major histocompatibility complex class II (MHC II) and presented via T-cell receptor (TCR) to a CD4+ T-cell (Figure 1). In addition to this initial interaction, the correct activation of the CD4+ T-cell requires a second positive signal that is stimulated by costimulatory molecules such as CD28 and B7 (CD80 and CD86). However, inhibitory signals, such as mediated by CTLA4 molecules, are capable of competing with CD28 for binding to B7, reducing T-cell expansion and production of cytokines [35]. T-cells that do not express the CTLA4-B7-inhibitory signal exhibit an unregulated proliferation of lymphocytes in the heart, which can lead to a severe damage of myocardium, and the development of cardiomyopathies [36, 37]. Cardiomyopathy patients present higher levels of CTLA4 SNP (+49A>G; Thr17Ala), which lead to a loss of function of CTLA4, than healthy subjects (14.7% vs. 7.4%, p = 0.005) [38]. Therefore, the correct activation of CD4+ T-cells in cardiac autoimmunity is mediated by (1) antigen-presenting cells that phagocytosed death cardiomyocytes or cardiac autoantigens and (2) a second co-stimulatory signal mediated by B7 (Figure 1). In addition to antigen-presenting cells, other cell types of non-hematopoietic lineage can also present antigens to CD4+ T-cells via MHC II under inflammatory stimuli [39]. It has been shown in patients and in rodent models that the MHC II expression by non-hematopoietic cells, in particular endothelial cells, contributes to the development of cardiomyopathy [40, 41]. Mice developed lower cardiac commitment when they did not express MHC II in endothelial cells [41]. Finally, properly activated CD4+ T-cells are able to activate B-lymphocytes to produce and secrete antibodies against cardiac antigens. The role of B-cells during the development of heart disease has been extensively studied [42]. The absence of programmed cell death protein-1 (PD-1), a key factor in the differentiation of B cells, can lead to the development of a severe form of dilated cardiomyopathy, with high levels of IgG that specifically binds to cardiomyocytes and induce apoptosis [43, 44]. Depletion of these B-cells recovers the heart failure phenotype in mice [42]. The production and release of autoantibodies is dependent of B-cell differentiation to plasma cells. During this process, there is a decrease in CD19 expression and maintenance of high levels of CD138 and transcription factor Blimp-1 [45]. The expression of these two factors is dependent of high levels of IL-17 and activation of autophagy. After this differentiation, it is possible to observe high titers of anti-myosin antibodies in BALB/c mice immunized with α-myosin heavy chain peptide (α-Myhc), particularly IgG2a and IgG2b subtypes, and the development of some cardiac impairment characteristics, such as the increase in the ratio of heart and body weight [46]. These antibodies can recognize and bind to specific cardiac antigens and deposited into the myocardium [47]. A wide range of evidence suggests that these autoantibodies directly affect cardiac function and physiology [48].

In addition to the response mediated by CD4+ T- and B-cells, CD8+ T-cytotoxic lymphocytes may be activated through the recognition of conjugated epitopes on MHC I. Damage induced by pathogen infection or cell stress mechanisms can alter intracellular protein processing resulting in misfolding, which will expose it to MHC I molecules. This will expose self-epitopes to autoreactive CD8+ T-cells (Figure 1A, B and D) [13]. Also, molecular mimicry may occur between pathogens and heart proteins (Figure 1B and D) [49]. This latter mechanism is well described in Chagas’ patients where antibodies against the B13 T. cruzi protein can also recognize cardiac α-Myhc (Figure 1D) [50]. This step via MHC I will promote the release of cytotoxic agents, such as perforin and granzyme B by CD8+ T-cells that could promote cardiomyocytes apoptosis and can amplify the release of cardiac antigens [51]. Throughout the modulation of immune system, lymphocytes will release cytokines that will expand autoreactive clones propagating the autoimmune response [11]. The autoimmune process formed by humoral and cellular responses can amplify the cardiac damage through the secretion of autoantibodies, cytokines, and other immune factors, despite initial stimuli.

Analysis of cardiomyopathy patients revealed the presence of autoantibodies against self-myocardial protein in up to 80% of the patients [52], indicating that autoimmunity is a central element for cardiomyopathy development. Evidence indicates that these autoantibodies affect the heart rather than other organs. Serum or IgG purified from these patients can induce negative inotropic effects on the heart of chicken embryos [53] and decrease heart contraction, the calcium transport [54, 55], and the diastolic relaxation in mice [48, 56]. The transference of IgG purified from patients serum with cardiac dysfunction to healthy mice induced significant necrosis in cardiomyocytes and mediated inflammatory effects with the aid of immune cells [57]. The characterization of these antibodies started in the 1980s and continues until today. Some of these antigens are listed in Table 1 [5869]. Most of produced autoantibodies directly recognize one specific cardiac antigen. But it has been demonstrated in rats that anti-myosin antibodies are capable to recognize the β1-adrenergic receptor and promotes their activation [70].

Class of cardiac proteinProteinFirst citation
G protein–coupled receptorsβ1 adrenergic receptor
2 muscarinic receptor
Limas et al., [58]
Fu et al., [59]
MitochondrialM7 antigen
Adenine nucleotide translocase (ANT)
Klein et al. [60]
Schultheiss et al. [61]
Structuralα-myosin heavy chain (MyHC)
Troponin I
Myosin-binding protein-C
Neu et al. [62]
Okazaki et al. [63]
Wolff et al. [64]
Müller et al. [65]
Müller et al. [65]
OthersNa-K ATPase
Proteasome 20 S
RNA-binding protein 20
Baba et al. [66]
Latif et al. [67]Voigt et al. [68]
Sánchez et al. [69]
Müller et al. [65]

Table 1.

Cardiac antigens characterized in autoimmune cardiomyopathies.

As briefly discussed above, the mechanisms that trigger the development of autoimmune cardiomyopathy are orchestrated by humoral and cellular responses. Immune cells such as granulocytes, monocytes, T-cells, B-cells, and mast cells infiltrate into the heart and promote the secretion of the cytokines, IL-17, -6, -1, -10, -12, IFN-γ, TGF-β, TNF-α, and chemokines that will generate an amplification loop, recruiting new inflammatory cells to the heart [7177]. However, the precise elucidation of this complex immune response mechanism remains unclear due to the difficulty to determine the precise order that immune cells infiltrate the heart [7880]. Once activated, this cellular response will undergo both beneficial and harmful effects as the disease progresses.

Data obtained in experimental autoimmune cardiomyopathy models using immunization with α-Myhc showed a predominance of CD4+ T-cell response [41, 77, 78, 81]. The transfer of CD4+ T-cells from mouse spleen that produced anti-myosin antibodies and developed cardiomyopathy mimics the disease in severe combined immunodeficiency (SCID) mice. On the contrary, CD8+ T-cell transference did not induce changes [32, 82]. Moreover, the depletion of CD4+ T-cells or treatment with anti-CD4 antibody prevents acute myocarditis with a decrease in the antibodies production and heart size [18, 83], confirming a prominent CD4+ T-cell role in this autoimmune cardiomyopathy model.

CD4+ T-lymphocytes can be biased to different profiles: Th1, Th2, Th17, Th9, Th22, follicular T (Tfh cells), and induced regulatory T (Treg cells) cells, each of which has a specialized function and is adapted to suppress a specific class of injuries or counteract the excessive activation of the immune system [84]. For autoimmune cardiomyopathy, the involvement of Th1, Th2, and Th17 cells has been characterized. The most relevant studies in this area are focused on Th1 and Th17 responses and their respective cytokines [32, 7173, 76, 8588].


3. IL-17 versus IFN-γ

Early studies using immunohistochemical assays identified the presence of cells producing mainly TNF-α and IL-1 in heart [89, 90]. In the early 2000 era, novel cytokines were identified in cardiomyopathic animal as IL-2 and IL-1-β [91]. In 2006, the first evidence of the IL-17 participation in autoimmune cardiomyopathy [76] was described.

In the last decade, Th17 cells have been extensively characterized in various autoimmune diseases [92, 93], including autoimmune cardiomyopathy [3, 80, 94]. Th17 CD4+ T-cells have been named after the discovery of their classical cytokine, IL-17A, but they also produce other effector cytokines including IL-17F, IL-22, and granulocyte macrophage-colony-stimulating factor (GM-CSF) [95]. Additionally, IL-17 may also be secreted by other cell types as Th17 CD8+ T-cells (Tc17), γδ T-cells (mainly in the skin and intestine), mucosal-associated invariant T-cells (MAIT), among other resident T-cells in different tissues [96, 97]. The polarization of CD4+ T-cells to Th17 profile initially requires the presence of TGF-β. This cytokine induces the expression of ROR-γt (RAR-related orphan receptor-γt) and FoxP3 (Forkhead box P3) transcriptional factors [98]. The co-expression of these two factors allows the physical connection between FoxP3 and ROR-γt inhibiting their differentiation to Th17. In the presence of IL-6, STAT3 is activated and interrupts the inhibition induced by FoxP3, resulting in the expression of IL-23 receptor and initiating the differentiation to Th17. Nevertheless, in the absence of IL-6, the inhibition of ROR-γt induced by FoxP3 will favor the development and expansion of Treg cells [99]. Beyond IL-6, IL-1-β is also capable of inhibiting FoxP3, generating an amplification loop [100, 101]. This cytokine polarization is very well characterized to CD4+ T-cells, but also appear to be responsible for differentiation of CD8+ T-cells to Tc17 profile [102, 103]. Recently, it was demonstrated that the differentiation of CD8+ T for IL-17 producing CD8+ T-cells is also dependent on the inhibition of Blimp-1 and T-bet [104]. Today, it is well accepted that the release of cytokines required for this process of differentiation, such as IL-6, IL-12, TNF-α, and IL-23 by antigen-presenting cells, such as dendritic cells and CD14+ monocyte, is induced by the recognition of cardiac autoantigens by TLR and by the presence of GM-CSF [105, 106]. As described, IL-6 and IL-23 will induce the differentiation of T helper (Th) cells to Th17 profile, where the release of IL-17 and more GM-CSF occurs, forming a positive feedback [88, 94].

Several works published in the last 10 years, using animal models and patients with cardiomyopathy, tried to establish IL-17 as a cytokine inducer of autoimmune cardiomyopathy. IL-17 was described as an important factor responsible for cardiac remodeling, fibrosis, and many other effects in the heart [72, 78, 86, 88]. An increase in IL-17 and IFN-γ transcriptional levels in mice that develop experimental autoimmune myocarditis (EAM) induced by subcutaneous inoculation with α-Myhc was observed. In this case, the copy number of IL-17 mRNA was about 20–30 times higher than those to IFN-γ [107].

It has been shown that the presence of IL-17 increases the expression of MMP-1 (matrix metalloproteinase-1), promoting the migration of cardiac fibroblasts in vitro and cardiac remodeling in vivo [108]. Furthermore, it was shown that Th17 cells and IL-17 were involved in survival, proliferation, and differentiation of B-cells [109]. In this direction, sera of patients with dilated cardiomyopathy showed an increase in IL-17 levels and in the frequency of Th17 cells when compared to health donors [109]. IL-17 neutralization or depletion slowed the development of autoimmune response and reduced the generation of cardiac autoantibodies in EAM myosin model [76, 110]. Also, mice treated with anti-IL-6, which were not capable of promoting the polarization of CD4+ T-cells to Th17 profile, do not develop autoimmune cardiomyopathy [111].

But these facts seem to be true only in the acute phase of the disease. After the establishment of a chronic condition, patients with cardiomyopathy presented lower levels of IL-17 and Th17 cells subtype [112]. So, high IL-17 levels are essential in acute phase of cardiomyopathy and for the progression to the final stage of the disease. But when the cardiomyopathy reaches this final stage, where heart dilatation is found, IL-17 seems not necessary [86, 87]. And even more, the reduction of IL-17 levels after the establishment of cardiac damage did not appear to be beneficial. In fact, mice infected with T. cruzi presenting typical functional cardiomyopathy changes, when treated with anti-IL17, developed an acute exacerbation of inflammation and cardiac dysfunction [113]. The absence of IL-17 receptor on infected mice also leads to the development of a fatal cardiomyopathy [114]. Additionally, it was demonstrated that individuals infected with T. cruzi who developed severe cardiac dysfunction had lower levels of IL-17 when compared with infected patients presenting moderate symptoms [115]. Recently, a study analyzed IL-17 levels in blood sample of 41 patients with dilated cardiomyopathy, without differentiating the etiology of the disease. They observed an increase in IL-17 levels up to 6 months after the diagnosis, but after 1 year of monitoring, IL-17 levels reduced close to those found in healthy patients, even in the presence of high levels of IL-6 and TGF-β [94]. This association between reduction in IL-17 levels and worse prognosis has also been found in patients who suffered acute myocardial infarction [116]. Finally, our research group recently showed that this relationship between IL-17 late decrease and worse symptoms occurred in heart disease of autoimmune origin. Mice that produce anti-M2AChR antibodies induced by gene immunization showed dilated cardiomyopathy and an increase in IL-17 production in the heart at 20-week postimmunization; however, with the progression of the disease to a final dilated stage, about 40 weeks after immunization, the IL-17 levels become comparable to the levels produced by the respective control animals [117]. The literature did not present explanations about the mechanisms involved in decreasing IL-17 levels. But IL-17 reduction, after the achievement of the disease, seems to be more harmful than beneficial to the development of cardiomyopathy. Thus, it is crucial to emphasize that the use of anti-IL-17 therapies for heart disease and other autoimmune diseases needs to be employed in a precise time to avoid harmful effects in the patients.

The immune response via Th1 cells and their cytokine marker IFN-γ is also largely related to autoimmune cardiomyopathy. During the innate immune response, IFN-γ is produced by natural killer cells and natural killer T-cells [118], as well as macrophages and dendritic cells [119]. In adaptive immunity, IFN-γ is mainly produced by CD8+ T-cells and Th1 CD4+ T-cells [120, 121]. After TCR stimulation, CD8+ T-cells produce higher levels of IFN-γ than CD4+ T-cells [122]. This is possible due to the interaction between TCR-MHC interaction that occurs between the CD8+ T-cells and MHC I-expressing antigen-presenting cells is sufficient to induce the secretion of IFN-γ and differentiation to a cytotoxic profile, whereas CD4+ T-cells need TCR recognition and a series of other stimuli [120]. IFN-γ also contributes to the switch process of IgG subclass in B-cells to a more pathogenic profile (IgG2a and IgG3 subclasses), activation of the complement system, inflammation, and tissue damage [123, 124]. But the IFN-γ expression is not static and confined to these classic subtype cells described above. Th17 cells can also produce IFN-γ concomitantly with IL-17 and even can become an exclusive IFN-γ producer [125, 126].

IFN-γ is an indicator of pathogenicity for autoimmune diseases [127], but its role in cardiomyopathies is still controversial [128] and it appears to be more protective than inducer of disease [76, 85, 129131]. For instance, mice treated with anti-IFN-γ antibodies or genetic deleted for T-bet, IFN-γ, or IFN-γR presented an exacerbated inflammatory infiltrates and increased heart size and its cavities [7173, 76, 85, 130]. One of the possible protective mechanisms mediated by IFN-γ involves the inhibition of autoreactive T-cell proliferation through the induction of nitric oxide synthase 2 enzyme (NOS2) and nitric oxide (NO) release [77, 132]. Although today this mechanism seems simple, its elucidation was very contradictory and troubled for some years. Initially, IL12Rβ1, one of the IL-12 receptor subunits, knockout mice were used for the study of participation of the IFN-γ in autoimmune cardiomyopathy. The inhibition of this classically Th1-polarizing pathway decreased the development of autoimmune cardiomyopathy in knockout mice, indicating the pathogenicity of Th1 cells [85]. However, as already mentioned, the IFN-γ−/− and IFN-γR−/− mice showed an exaggerated and lethal disease [72, 73], an apparent contradictory result. This impasse was resolved when it was shown that β1 subunit of the receptor for IL-12 was shared with the IL-23 receptor, inducer of Th17 response [110]. Despite all this characterization of IFN-γ-protective role, it is unclear which mechanisms are activated during this process. It is known that high levels of IFN-γ induce the production of NO by NOS2 with consequently inhibition of CD4+ T-cells autoreactive proliferation [77]. HL-1 cell line and primary cardiomyocytes treated with IFN-γ showed an activation of absent in melanoma 2 (AIM-2), an intracellular receptor of the PRRs family, which reduces IL-6, IP-10 (inducible protein 10, CXCL10), and TNF-α transcription in cardiomyocytes and limits inflammation in cardiomyocytes, but not in cardiac fibroblasts [133]. Also, high IFN-γ levels secreted by γδ cells could kill pathogenic F4/80+ macrophages in heart and control cardiac damage [134]. There could be some explanation for how IFN-γ protects mice from the development of autoimmune cardiomyopathy.

Meanwhile, several other studies demonstrated the ability of high IFN-γ levels in inducing myocardial inflammation, interstitial fibrosis, apoptosis, wall thinning, systolic dysfunction, dilatation, and cardiomyopathy [128]. And more recently, it has been shown that IFN-γ has the capacity to induce cardiac damage in autoimmune cardiomyopathy model. High IFN-γ levels were associated with cardiorespiratory commitment, electrical abnormalities, and cardiac dilatation. This situation was more prominent in the absence of purinergic receptor P2X7 [117]. These evidences show that it is not possible to withdraw the IFN-γ participation as a cardiomyopathy inducer.


4. Immune cells’ function on autoimmune cardiomyopathy

The entire description and discussion made so far focused mainly on the presence and polarization of CD4+ T-cells; however, as already pointed out, the presence and participation of other immune cells can be decisive in disease severity. In genetically susceptible mouse model, preferably BALB/c, immunization with the α-Myhc in the presence of a strong adjuvant, like complete Freund’s adjuvant (CFA), the disease is mediated almost exclusively by CD4+ T-cells. However, it has been recently identified in EAM-induced A/J mice that the α-Myhc338-348 epitope was the immune dominant for CD8+ response [135]. In this case, they showed antibodies production, cardiomyopathy development, and the presence of inflammatory infiltrate composed of 35% of CD8+ T-cells [135]. As previously mentioned, this infiltration of CD8+ T-cells has a high cytotoxic role as a source of IFN-γ, perforin, and granzyme that will induce irreversible damage to cardiomyocytes [51].

Despite the great importance of T-cells, it is believed that the major cells infiltrating the hearts during the development of cardiomyopathy are monocytes, especially CD11b+ [77]. These cells can differentiate into different profiles ranging from dendritic cells, macrophages, and fibroblasts depending on the immune environment (including cytokines, chemokines, and growth factors) present in the heart [77, 132, 136]. The more severe cardiomyopathy is found when there is the presence of eosinophils in the heart infiltration [131]. It is believed that NK cells control the exacerbated proliferation of eosinophils in the heart through direct induction of apoptosis [137]. The recruitment of eosinophils to the heart can also be controlled by cardiac fibroblasts and F4/80+ macrophages through the release of CCL11 and CCL24 (eotaxin-1 and eotaxin-2), respectively [138].

In the healthy heart, it is possible to find a population of resident macrophages, but the number of these cells can be expanded after the infiltration of new macrophages under some stimulus such as initiators of the autoimmune cardiomyopathy, cited at the beginning of this review (Figure 1). Macrophage infiltration is a well-known step, but it is little studied in cardiomyopathy [139]. These cells can differentiate into various profiles depending on the cytokine present in the medium. Some of these profiles are classically activated, pro-inflammatory M1 macrophages and alternatively activated, anti-inflammatory M2-polarized macrophages, tumor-associated macrophages (TAM), “immature” monocyte-like (GR1/Ly6C+) or “mature” neutrophil-like (GR1/Ly6G+), and suppressor cells derived from myeloid precursor (MDSCs) [79]. The functional properties and secretory profile of macrophages likely promote myocardial health or disease. In some cases, their influence on acute inflammation and chronic fibrosis is well described, and in others, their cardioprotective function seems to be almost indisputable, being proposed as a good source of treatment [140142]. In models of cardiac autoimmunity, there is a predominance of M2 macrophages, around 70%, which promoted the resolution of the disease in heart tissue after damage. And with the presence of M1 macrophages, there is the expansion of Th17 cells and cardiac dilation [79, 143145]. Therefore, further studies about the importance and function of macrophages in cardiomyopathies, in particular autoimmune ones, are needed.


5. Conclusion

The findings described in this chapter demonstrate the existence of a precise balance of the immune response, where a complex network of factors creates the conditions for the progression of autoimmune cardiomyopathy and dictates its severity. The combination of present and future knowledge on this line of study can ultimately guide to a possible effective and non-general treatment. However, two factors must be taken into consideration: (1) the correct association between anti-humoral and anti-cytokine therapies and (2) the period where the treatment must be applied.

Therefore, the participation of IFN-γ and IL-17 in the autoimmunity development recalls us a dance instead of an arms race, where a fine temporal and quantitative control of these cytokines can determine the cardiomyopathy evolution.



Sources of funding for this work were from the Fundação de Amparo a Pesquisa do Rio de Janeiro – FAPERJ/Temáticos and Instituto Nacional para Pesquisa Translacional em Saúde e Ambiente na Região Amazônica – INPETAM, Conselho Nacional de Desenvolvimento Científico e Tecnológico/MCT. We thank Dr Pedro Muanis Persechini and Dr Rafael Soares Aquino for review and final formatting of this review. The authors declare that they have no conflicts of interest.


  1. 1. BJ Maron, JA Towbin, G Thiene, C Antzelevitch, D Corrado, D Arnett, AJ Moss, CE Seidman, and JB Young. Contemporary definitions and classification of the cardiomyopathies an American heart association scientific statement from the council on clinical cardiology, heart failure and transplantation committee; quality of care and outcomes research and functional genomics and translational biology interdisciplinary working groups; and council on epidemiology and prevention. Circulation. 2006; 113:1807–1816. DOI: 10.1161/CIRCULATIONAHA.106.174287.
  2. 2. GV Ramani, PA Uber, and MR Mehra. Chronic heart failure: contemporary diagnosis and management. Mayo Clinic Proceedings. 2010; 85:180–195. DOI: 10.4065/mcp.2009.0494.
  3. 3. NR Rose. Myocarditis: infection versus autoimmunity. Journal of Clinical Immunology. 2009; 29:730–737. DOI: 10.1007/s10875-009-9339-z.
  4. 4. T Shaw, P Elliott, and WJ McKenna. Dilated cardiomyopathy: a genetically heterogeneous disease. The Lancet. 2002; 360:654–655. DOI: 10.1016/S0140-6736(02)09879-3.
  5. 5. M Harakalova, G Kummeling, A Sammani, M Linschoten, AF Baas, J van der Smagt, PA Doevendans, JP van Tintelen, D Dooijes, and M Mokry. A systematic analysis of genetic dilated cardiomyopathy reveals numerous ubiquitously expressed and muscle-specific genes. European Journal of Heart Failure. 2015; 17:484–493. DOI: 10.1002/ejhf.255.
  6. 6. DS Herman, L Lam, MR Taylor, L Wang, P Teekakirikul, D Christodoulou, L Conner, SR DePalma, B McDonough, and E Sparks. Truncations of titin causing dilated cardiomyopathy. New England Journal of Medicine. 2012; 366:619–628. DOI: 10.1056/NEJMoa1110186.
  7. 7. RE Hershberger and JD Siegfried. Update 2011: clinical and genetic issues in familial dilated cardiomyopathy. Journal of the American College of Cardiology. 2011; 57:1641–1649. DOI: 10.1016/j.jacc.2011.01.015.
  8. 8. YM Pinto, PM Elliott, E Arbustini, Y Adler, A Anastasakis, M Böhm, D Duboc, J Gimeno, P de Groote, and M Imazio. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. European Heart Journal. 2016; 37:1850–1858. DOI: 10.1093/eurheartj/ehv727.
  9. 9. J Staab, V Ruppert, S Pankuweit, and T Meyer. Polymorphisms in genes encoding nonsarcomeric proteins and their role in the pathogenesis of dilated cardiomyopathy. Herz. 2012; 37:836–842. DOI: 10.1007/s00059-012-3698-6.
  10. 10. S Pankuweit, V Ruppert, u Jónsdóttir, H-H Müller, T Meyer, and GCNoH Failure. The HLA class II allele DQB1* 0309 is associated with dilated cardiomyopathy. Gene. 2013; 531:180–183.
  11. 11. JM Lappé, CM Pelfrey, and WW Tang. Recent insights into the role of autoimmunity in idiopathic dilated cardiomyopathy. Journal of Cardiac Failure. 2008; 14:521–530. DOI: 10.1016/j.cardfail.2008.02.016.
  12. 12. GM Felker, RE Thompson, JM Hare, RH Hruban, DE Clemetson, DL Howard, KL Baughman, and EK Kasper. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. New England Journal of Medicine. 2000; 342:1077–1084. DOI: 10.1056/NEJM200004133421502.
  13. 13. S Pankuweit, V Ruppert, and B Maisch. Inflammation in dilated cardiomyopathy. Herz. 2004; 29:788–793. DOI: 10.1007/s00059-004-2626-9.
  14. 14. H Mahrholdt, A Wagner, CC Deluigi, E Kispert, S Hager, G Meinhardt, H Vogelsberg, P Fritz, J Dippon, and C-T Bock. Presentation, patterns of myocardial damage, and clinical course of viral myocarditis. Circulation. 2006; 114:1581–1590. DOI: 10.1161/CIRCULATIONAHA.105.606509.
  15. 15. U Kühl, M Pauschinger, B Seeberg, D Lassner, M Noutsias, W Poller, and H-P Schultheiss. Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation. 2005; 112:1965–1970. DOI: 10.1161/CIRCULATIONAHA.105.548156.
  16. 16. T Leslie Jr, A Keren, K Sliwa, A Matsumori, and GA Mensah. The global burden of myocarditis. Global Heart. 2014; 9:121–129. DOI: 10.1016/j.gheart.2014.01.007.
  17. 17. EA Bocchi, FGM Braga, SMA Ferreira, LEP Rohde, WAd Oliveira, DRd Almeida, MdCV Moreira, RB Bestetti, S Bordignon, and C Azevedo. III Brazilian Guideline for Insufficiency Chronic heart disease. Brazilian Archives of Cardiology. 2009; 93:3–70. DOI: 10.1590/S0066-782X2009002000001
  18. 18. T Yoshikawa, A Baba, and Y Nagatomo. Autoimmune mechanisms underlying dilated cardiomyopathy. Circulation Journal. 2009; 73:602–607. DOI: 10.1253/circj.CJ-08-1151.
  19. 19. N Bodyak, PM Kang, M Hiromura, I Sulijoadikusumo, N Horikoshi, K Khrapko, and A Usheva. Gene expression profiling of the aging mouse cardiac myocytes. Nucleic Acids Research. 2002; 30:3788–3794. DOI: 10.1093/nar/gkf497.
  20. 20. KM Bonney and DM Engman. Chagas heart disease pathogenesis: one mechanism or many? Current Molecular Medicine. 2008; 8:510–518. DOI: 10.2174/156652408785748004.
  21. 21. Z Cai, L Shen, H Ma, J Yang, D Yang, H Chen, J Wei, Q Lu, DW Wang, and M Xiang. Involvement of endoplasmic reticulum stress-mediated C/EBP homologous protein activation in coxsackievirus B3-induced acute viral myocarditis. Circulation: Heart Failure. 2015; 8:809–818. DOI: 10.1161/CIRCHEARTFAILURE.114.001244.
  22. 22. G Gao, J Zhang, X Si, J Wong, C Cheung, B McManus, and H Luo. Proteasome inhibition attenuates coxsackievirus-induced myocardial damage in mice. American Journal of Physiology-Heart and Circulatory Physiology. 2008; 295:H401–H408. DOI: 10.1152/ajpheart.00292.2008.
  23. 23. S Akira, S Uematsu, and O Takeuchi. Pathogen recognition and innate immunity. Cell. 2006; 124:783–801. DOI: 10.1016/j.cell.2006.02.015.
  24. 24. L Lin and AA Knowlton. Innate immunity and cardiomyocytes in ischemic heart disease. Life Sciences. 2014; 100:1–8. DOI: 10.1016/j.lfs.2014.01.062.
  25. 25. KL Rock, E Latz, F Ontiveros, and H Kono. The sterile inflammatory response. Annual Review of Immunology. 2010; 28:321–342. DOI: 10.1146/annurev-immunol-030409-101311.
  26. 26. JH Boyd, S Mathur, Y Wang, RM Bateman, and KR Walley. Toll-like receptor stimulation in cardiomyocytes decreases contractility and initiates an NF-κB dependent inflammatory response. Cardiovascular Research. 2006; 72:384–393. DOI: 10.1016/j.cardiores.2006.09.011.
  27. 27. C Lipps, JH Nguyen, L Pyttel, TL Lynch, C Liebetrau, G Aleshcheva, S Voss, O Dörr, HM Nef, and H Möllmann. N-terminal fragment of cardiac myosin binding protein-C triggers pro-inflammatory responses in vitro. Journal of Molecular and Cellular Cardiology. 2016; 99:47–56. DOI: 10.1016/j.yjmcc.2016.09.003.
  28. 28. PP Pagni, S Traub, O Demaria, L Chasson, and L Alexopoulou. Contribution of TLR7 and TLR9 signaling to the susceptibility of MyD88-deficient mice to myocarditis. Autoimmunity. 2010; 43:275–287. DOI: 10.3109/08916930903509056.
  29. 29. KJ Jensen, FS Garmaroudi, J Zhang, J Lin, S Boroomand, M Zhang, Z Luo, D Yang, H Luo, and BM McManus. An ERK-p38 subnetwork coordinates host cell apoptosis and necrosis during coxsackievirus B3 infection. Cell Host & Microbe. 2013; 13:67–76. DOI: 10.1016/j.chom.2012.11.009.
  30. 30. AM Orogo and ÅB Gustafsson. Cell death in the myocardium: my heart won't go on. IUBMB life. 2013; 65:651–656.
  31. 31. A Piek, R de Boer, and H Silljé. The fibrosis-cell death axis in heart failure. Heart Failure Reviews. 2016; 21:199–211. DOI: 10.1007/s10741-016-9536-9.
  32. 32. U Eriksson, R Ricci, L Hunziker, MO Kurrer, GY Oudit, TH Watts, I Sonderegger, K Bachmaier, M Kopf, and JM Penninger. Dendritic cell–induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nature Medicine. 2003; 9:1484–1490. DOI: 10.1038/nm960
  33. 33. E Wan, X-Y Yeap, S Dehn, RL Terry, ML Novak, S Zhang, S Iwata, X Han, S Homma, and K Drosatos. Enhanced efferocytosis of apoptotic cardiomyocytes through MER tyrosine kinase links acute inflammation resolution to cardiac repair after infarction. Circulation Research. 2013; 113:1004–1012. DOI: 10.1161/CIRCRESAHA.113.301198.
  34. 34. O Joffre, MA Nolte, and R Spörri. Inflammatory signals in dendritic cell activation and the induction of adaptive immunity. Immunological Reviews. 2009; 227:234–247. DOI: 10.1111/j.1600-065X.2008.00718.x.
  35. 35. T Pentcheva-Hoang, JG Egen, K Wojnoonski, and JP Allison. B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity. 2004; 21:401–413. DOI: 10.1016/j.immuni.2004.06.017.
  36. 36. A Ligers, N Teleshova, T Masterman, W Huang, and J Hillert. CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms. Genes and Immunity. 2001; 2:145–152. DOI: 10.1038/sj.gene.6363752.
  37. 37. EA Tivol, F Borriello, AN Schweitzer, WP Lynch, JA Bluestone, and AH Sharpe. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995; 3:541–547. DOI: 10.1016/1074-7613(95)90125-6.
  38. 38. V Ruppert, T Meyer, C Struwe, J Petersen, A Perrot, MG Posch, C Özcelik, A Richter, B Maisch, and S Pankuweit. Evidence for CTLA4 as a susceptibility gene for dilated cardiomyopathy. European Journal of Human Genetics. 2010; 18:694–699. DOI: 10.1038/ejhg.2010.3.
  39. 39. T Kambayashi and TM Laufer. Atypical MHC class II-expressing antigen-presenting cells: can anything replace a dendritic cell? Nature Reviews Immunology. 2014; 14:719–730. DOI: 10.1038/nri3754.
  40. 40. AL Caforio, JT Stewart, E Bonifacio, M Burke, MJ Davies, WJ McKenna, and GF Bottazzo. Inappropriate major histocompatibility complex expression on cardiac tissue in dilated cardiomyopathy. Relevance for autoimmunity? Journal of Autoimmunity. 1990; 3:187–200. DOI: 10.1016/0896-8411(90)90140-N.
  41. 41. C Thelemann, S Haller, P Blyszczuk, G Kania, M Rosa, U Eriksson, S Rotman, W Reith, and H Acha-Orbea. Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis. European Journal of Immunology. 2015; 46:656–664.
  42. 42. AM Cordero-Reyes, KA Youker, AR Trevino, R Celis, DJ Hamilton, JH Flores-Arredondo, CM Orrego, A Bhimaraj, JD Estep, and G Torre-Amione. Full Expression of cardiomyopathy is partly dependent on B-cells: a pathway that involves cytokine activation, immunoglobulin deposition, and activation of apoptosis. Journal of the American Heart Association. 2016; 5:e002484.
  43. 43. H Nishimura, T Okazaki, Y Tanaka, K Nakatani, M Hara, A Matsumori, S Sasayama, A Mizoguchi, H Hiai, and N Minato. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001; 291:319–322. DOI: 10.1126/science.291.5502.319.
  44. 44. M-L Thibult, E Mamessier, J Gertner-Dardenne, S Pastor, S Just-Landi, L Xerri, B Chetaille, and D Olive. PD-1 is a novel regulator of human B-cell activation. International Immunology. 2013; 25:129–137. DOI: 10.1093/intimm/dxs098.
  45. 45. KL Calame. Plasma cells: finding new light at the end of B cell development. Nature Immunology. 2001; 2:1103–1108. DOI: 10.1038/ni1201-1103.
  46. 46. J Yuan, M Yu, H-H Li, Q Long, W Liang, S Wen, M Wang, H-P Guo, X Cheng, and Y-H Liao. Autophagy contributes to IL-17-induced plasma cell differentiation in experimental autoimmune myocarditis. International Immunopharmacology. 2014; 18:98–105. DOI: 10.1016/j.intimp.2013.11.008.
  47. 47. AM Cordero-Reyes, KA Youker, and G Torre-Amione. The role of b-cells in heart failure. Methodist DeBakey Cardiovascular Journal. 2013; 9:15–19. DOI: 10.14797/mdcj-9-1-15.
  48. 48. R Jahns, V Boivin, L Hein, S Triebel, CE Angermann, G Ertl, and MJ Lohse. Direct evidence for a β 1-adrenergic receptor–directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. The Journal of Clinical Investigation. 2004; 113:1419–1429. DOI: 10.1172/JCI20149.
  49. 49. U Nussinovitch and Y Shoenfeld. The diagnostic and clinical significance of anti-muscarinic receptor autoantibodies. Clinical Reviews in Allergy & Immunology. 2012; 42:298–308. DOI: 10.1007/s12016-010-8235-x.
  50. 50. E Cunha-Neto, M Duranti, A Gruber, B Zingales, I De Messias, N Stolf, G Bellotti, ME Patarroyo, F Pilleggi, and J Kalil. Autoimmunity in Chagas disease cardiopathy: biological relevance of a cardiac myosin-specific epitope crossreactive to an immunodominant Trypanosoma cruzi antigen. Proceedings of the National Academy of Sciences. 1995; 92:3541–3545.
  51. 51. JC Silverio, LM De Oliveira Pinto, AA Da Silva, GM De Oliveira, and J Lannes-Vieira. Perforin-expressing cytotoxic cells contribute to chronic cardiomyopathy in Trypanosoma cruzi infection. International Journal of Experimental Pathology. 2010; 91:72–86. DOI: 10.1111/j.1365-2613.2009.00670.x.
  52. 52. JL Winters. Apheresis in the treatment of idiopathic dilated cardiomyopathy. Journal of Clinical Apheresis. 2012; 27:312–319. DOI: 10.1002/jca.21245.
  53. 53. A Baba and M Fu. Autoantibodies in atrial fibrillation: actor, biomarker or bystander? Autoimmunity. 2008; 41:470–472. DOI: 10.1080/08916930802031504.
  54. 54. SB Felix, A Staudt, M Landsberger, Y Grosse, V Stangl, T Spielhagen, G Wallukat, KD Wernecke, G Baumann, and K Stangl. Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption. Journal of the American College of Cardiology. 2002; 39:646–652. DOI: 10.1016/S0735-1097(01)01794-6.
  55. 55. J Chen, L Larsson, E Haugen, O Fedorkova, E Angwald, F Waagstein, and M Fu. Effects of autoantibodies removed by immunoadsorption from patients with dilated cardiomyopathy on neonatal rat cardiomyocytes. European Journal of Heart Failure. 2006; 8:460–467. DOI: 10.1016/j.ejheart.2005.10.019.
  56. 56. Y Staudt, C Trimpert, K Birkenmeier, T Krieg, T Bemmann, D Beug, S Felix, and A Staudt. Effects of antibodies obtained from patients with dilated cardiomyopathy on the function of isolated rat hearts. European Journal of Clinical Investigation. 2006; 36:85–90. DOI: 10.1111/j.1365-2362.2006.01603.x.
  57. 57. AL Caforio, A Angelini, M Blank, A Shani, S Kivity, G Goddard, A Doria, A Schiavo, M Testolina, and S Bottaro. Passive transfer of affinity-purified anti-heart autoantibodies (AHA) from sera of patients with myocarditis induces experimental myocarditis in mice. International Journal of Cardiology. 2015; 179:166–177. DOI: 10.1016/j.ijcard.2014.10.165.
  58. 58. CJ Limas, IF Goldenberg, and C Limas. Autoantibodies against beta-adrenoceptors in human idiopathic dilated cardiomyopathy. Circulation Research. 1989; 64:97–103. DOI: 10.1161/01.RES.64.1.97.
  59. 59. L-X Fu, Y Magnusson, C-H Bergh, J Liljeqvist, F Waagstein, A Hjalmarson, and J Hoebeke. Localization of a functional autoimmune epitope on the muscarinic acetylcholine receptor-2 in patients with idiopathic dilated cardiomyopathy. Journal of Clinical Investigation. 1993; 91:1964–1968. DOI: 10.1172/JCI116416.
  60. 60. R Klein, B Maisch, K Kochsiek, and P Berg. Demonstration of organ specific antibodies against heart mitochondria (anti-M7) in sera from patients with some forms of heart diseases. Clinical and Experimental Immunology. 1984; 58:283–292.
  61. 61. H-P Schultheiss. Dysfunction of the ADP/ATP carrier as a causative factor for the disturbance of the myocardial energy metabolism in dilated cardiomyopathy. Basic Research in Cardiology. 1992; 87:311–320.
  62. 62. N Neu, NR Rose, KW Beisel, A Herskowitz, G Gurri-Glass, and SW Craig. Cardiac myosin induces myocarditis in genetically predisposed mice. The Journal of Immunology. 1987; 139:3630–3636.
  63. 63. T Okazaki, Y Tanaka, R Nishio, T Mitsuiye, A Mizoguchi, J Wang, M Ishida, H Hiai, A Matsumori, and N Minato. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nature Medicine. 2003; 9:1477–1483. DOI: 10.1038/nm955.
  64. 64. PG Wolff, U Kühl, and H-P Schultheiss. Laminin distribution and autoantibodies to laminin in dilated cardiomyopathy and myocarditis. American Heart Journal. 1989; 117:1303–1309. DOI: 10.1016/0002-8703(89)90410-9.
  65. 65. A-M Müller, M Bockstahler, G Hristov, C Weiß, A Fischer, S Korkmaz-Icöz, E Giannitsis, W Poller, H-P Schultheiss, and HA Katus. Identification of novel antigens contributing to autoimmunity in cardiovascular diseases. Clinical Immunology. 2016; 170:30370–30379. DOI: 10.1016/j.clim.2016.09.003.
  66. 66. A Baba, T Yoshikawa, and S Ogawa. Autoantibodies produced against sarcolemmal Na-K-ATPase: possible upstream targets of arrhythmias and sudden death in patients with dilated cardiomyopathy. Journal of the American College of Cardiology. 2002; 40:1153–1159. DOI: 10.1016/S0735-1097(02)02075-2.
  67. 67. N Latif, CS Baker, MJ Dunn, ML Rose, P Brady, and MH Yacoub. Frequency and specificity of antiheart antibodies in patients with dilated cardiomyopathy detected using SDS-PAGE and western blotting. Journal of the American College of Cardiology. 1993; 22:1378–1384. DOI: 10.1016/0735-1097(93)90546-D.
  68. 68. A Voigt, K Bartel, K Egerer, C Trimpert, E Feist, C Gericke, R Kandolf, K Klingel, U Kuckelkorn, and K Stangl. Humoral anti-proteasomal autoimmunity in dilated cardiomyopathy. Basic Research in Cardiology. 2010; 105:9–18. DOI: 10.1007/s00395-009-0061-z.
  69. 69. D Sánchez, P Gregor, K Čurila, I Hoffmanová, V Hábová, L Tučková, and H Tlaskalová-Hogenová. Anti-calreticulin antibodies and calreticulin in sera of patients diagnosed with dilated or hypertrophic cardiomyopathy. Autoimmunity. 2016; 30:1–9. DOI: 10.1080/08916934.2016.1214822.
  70. 70. Y Li, JS Heuser, LC Cunningham, SD Kosanke, and MW Cunningham. Mimicry and antibody-mediated cell signaling in autoimmune myocarditis. The Journal of Immunology. 2006; 177:8234–8240. DOI: 10.4049/​jimmunol.177.11.8234.
  71. 71. M Afanasyeva, D Georgakopoulos, and NR Rose. Autoimmune myocarditis: cellular mediators of cardiac dysfunction. Autoimmunity Reviews. 2004; 3:476–486. DOI: 10.1016/j.autrev.2004.08.009.
  72. 72. U Eriksson, M Kurrer, R Bingisser, H Eugster, P Saremaslani, F Follath, S Marsch, and U Widmer. Lethal autoimmune myocarditis in interferon-γ receptor–deficient mice enhanced disease severity by impaired inducible nitric oxide synthase induction. Circulation. 2001; 103:18–21. DOI: 10.1161/01.CIR.103.1.18.
  73. 73. U Eriksson, MO Kurrer, N Schmitz, SC Marsch, A Fontana, H-P Eugster, and M Kopf. Interleukin-6–deficient mice resist development of autoimmune myocarditis associated with impaired upregulation of complement C3. Circulation. 2003; 107:320–325. DOI: 10.1161/01.CIR.0000043802.38699.66.
  74. 74. H Higuchi, M Hara, K Yamamoto, T Miyamoto, M Kinoshita, T Yamada, K Uchiyama, and A Matsumori. Mast cells play a critical role in the pathogenesis of viral myocarditis. Circulation. 2008; 118:363–372. DOI: 10.1161/CIRCULATIONAHA.107.741595.
  75. 75. T Nossuli, V Lakshminarayanan, G Baumgarten, G Taffet, C Ballantyne, L Michael, and M Entman. A chronic mouse model of myocardial ischemia-reperfusion: essential in cytokine studies. American Journal of Physiology-Heart and Circulatory Physiology. 2000; 278:H1049–H1055.
  76. 76. M Rangachari, N Mauermann, RR Marty, S Dirnhofer, MO Kurrer, V Komnenovic, JM Penninger, and U Eriksson. T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17. The Journal of Experimental Medicine. 2006; 203:2009–2019. DOI: 10.1084/jem.20052222.
  77. 77. A Valaperti, RR Marty, G Kania, D Germano, N Mauermann, S Dirnhofer, B Leimenstoll, P Blyszczuk, C Dong, and C Mueller. CD11b+ monocytes abrogate Th17 CD4+ T cell-mediated experimental autoimmune myocarditis. The Journal of Immunology. 2008; 180:2686–2695. DOI: 10.4049/​jimmunol.180.4.2686.
  78. 78. P Chen, G Baldeviano, D Ligons, M Talor, J Barin, N Rose, and D Cihakova. Susceptibility to autoimmune myocarditis is associated with intrinsic differences in CD4+ T cells. Clinical & Experimental Immunology. 2012; 169:79–88. DOI: 10.1111/j.1365-2249.2012.04598.x.
  79. 79. D Fairweather and D Cihakova. Alternatively activated macrophages in infection and autoimmunity. Journal of Autoimmunity. 2009; 33:222–230. DOI: 10.1016/j.jaut.2009.09.012.
  80. 80. N Rose. Critical cytokine pathways to cardiac inflammation. Journal of Interferon & Cytokine Research. 2011; 31:705–710. DOI: 10.1089/jir.2011.0057.
  81. 81. M Noutsias, M Rohde, K Göldner, A Block, K Blunert, L Hemaidan, M Hummel, JH Blohm, D Lassner, and U Kühl. Expression of functional T-cell markers and T-cell receptor Vbeta repertoire in endomyocardial biopsies from patients presenting with acute myocarditis and dilated cardiomyopathy. European Journal of Heart Failure. 2011; 13:611–618.
  82. 82. K Tajiri, N Shimojo, S Sakai, T Machino-Ohtsuka, K Imanaka-Yoshida, M Hiroe, Y Tsujimura, T Kimura, A Sato, and Y Yasutomi. Pitavastatin regulates helper T-cell differentiation and ameliorates autoimmune myocarditis in mice. Cardiovascular Drugs and Therapy. 2013; 27:413–424. DOI: 10.1007/s10557-013-6464-y.
  83. 83. SA Huber, AM Feldman, and D Sartini. Coxsackievirus B3 induces T regulatory cells, which inhibit cardiomyopathy in tumor necrosis factor-α transgenic mice. Circulation Research. 2006; 99:1109–1116. DOI: 10.1161/01.RES.0000249405.13536.49.
  84. 84. JT Chang, EJ Wherry, and AW Goldrath. Molecular regulation of effector and memory T cell differentiation. Nature Immunology. 2014; 15:1104–1115. DOI: 10.1038/ni.3031.
  85. 85. M Afanasyeva, Y Wang, Z Kaya, EA Stafford, KM Dohmen, AAS Akha, and NR Rose. Interleukin-12 receptor/STAT4 signaling is required for the development of autoimmune myocarditis in mice by an interferon-γ-independent pathway. Circulation. 2001; 104:3145–3151. DOI: 10.1161/hc5001.100629.
  86. 86. GC Baldeviano, JG Barin, MV Talor, S Srinivasan, D Bedja, D Zheng, K Gabrielson, Y Iwakura, NR Rose, and D Cihakova. Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy. Circulation Research. 2010; 106:1646–1655. DOI: 10.1161/CIRCRESAHA.109.213157.
  87. 87. V Nindl, R Maier, D Ratering, R De Giuli, R Züst, V Thiel, E Scandella, F Di Padova, M Kopf, and M Rudin. Cooperation of Th1 and Th17 cells determines transition from autoimmune myocarditis to dilated cardiomyopathy. European Journal of Immunology. 2012; 42:2311–2321. DOI: 10.1002/eji.201142209.
  88. 88. L Wu, NL Diny, S Ong, JG Barin, X Hou, NR Rose, MV Talor, and D Čiháková. Pathogenic IL-23 signaling is required to initiate GM-CSF-driven autoimmune myocarditis in mice. European journal of immunology. 2016; 46:582–592.
  89. 89. J Lane, DA Neumann, A Lafond-Walker, A Herskowitz, and NR Rose. Interleukin 1 or tumor necrosis factor can promote Coxsackie B3-induced myocarditis in resistant B10. A mice. The Journal of Experimental Medicine. 1992; 175:1123–1129. DOI: 10.1084/jem.175.4.1123.
  90. 90. D Neumann, J Lane, G Allen, A Herskowitz, and N Rose. Viral myocarditis leading to cardiomyopathy: do cytokines contribute to pathogenesis? Clinical Immunology and Immunopathology. 1993; 68:181–190. DOI: 10.1006/clin.1993.1116.
  91. 91. Y Wang, M Afanasyeva, SL Hill, Z Kaya, and NR Rose. Nasal administration of cardiac myosin suppresses autoimmune myocarditis in mice. Journal of the American College of Cardiology. 2000; 36:1992–1999. DOI: 10.1016/S0735-1097(00)00939-6.
  92. 92. A Awasthi and VK Kuchroo. Th17 cells: from precursors to players in inflammation and infection. International Immunology. 2009; 21:489–498. DOI: 10.1093/intimm/dxp021.
  93. 93. T Korn, E Bettelli, M Oukka, and VK Kuchroo. IL-17 and Th17 Cells. Annual Review of Immunology. 2009; 27:485–517. DOI: 10.1146/annurev.immunol.021908.132710.
  94. 94. JM Myers, LT Cooper, DC Kem, S Stavrakis, SD Kosanke, EM Shevach, D Fairweather, JA Stoner, CJ Cox, and MW Cunningham. Cardiac myosin-Th17 responses promote heart failure in human myocarditis. JCI Insight. 2016; 1.
  95. 95. Y Lee, A Awasthi, N Yosef, FJ Quintana, S Xiao, A Peters, C Wu, M Kleinewietfeld, S Kunder, and DA Hafler. Induction and molecular signature of pathogenic Th17 cells. Nature Immunology. 2012; 13:991–999. DOI: 10.1038/ni.2416.
  96. 96. A Beringer, M Noack, and P Miossec. IL-17 in chronic inflammation: from discovery to targeting. Trends in Molecular Medicine. 2016; 22:230–241. DOI: 10.1016/j.molmed.2016.01.001.
  97. 97. S Rutz, C Eidenschenk, JR Kiefer, and W Ouyang. Post-translational regulation of RORγt—A therapeutic target for the modulation of interleukin-17-mediated responses in autoimmune diseases. Cytokine & Growth Factor Reviews. 2016; 30:1–17. DOI: 10.1016/j.cytogfr.2016.07.004.
  98. 98. ML Diller, RR Kudchadkar, KA Delman, DH Lawson, and ML Ford. Balancing inflammation: The link between Th17 and regulatory T cells. Mediators of Inflammation. 2016; 2016: 6309219-6309227. DOI:10.1155/2016/6309219..
  99. 99. L Zhon, J Lopes, and M Chong. TGF-beta-induced Foxp3 inhibits Thl7 cell differentiation by antagonizing ROR gamma function E J. Nature. 2008; 453:236–240.
  100. 100. N Komatsu, K Okamoto, S Sawa, T Nakashima, M Oh-Hora, T Kodama, S Tanaka, JA Bluestone, and H Takayanagi. Pathogenic conversion of Foxp3+ T cells into Th17 cells in autoimmune arthritis. Nature Medicine. 2014; 20:62–68. DOI: 10.1038/nm.3432.
  101. 101. S Okada, H Inoue, K Yamauchi, H Iijima, Y Ohkawara, T Takishima, and K Shirato. Potential role of interleukin-1 in allergen-induced late asthmatic reactions in guinea pigs: suppressive effect of interleukin-1 receptor antagonist on late asthmatic reaction. Journal of Allergy and Clinical Immunology. 1995; 95:1236–1245. DOI: 10.1016/S0091-6749(95)70081-1.
  102. 102. PK Dagur, A Biancotto, E Stansky, HN Sen, RB Nussenblatt, and JP McCoy. Secretion of interleukin-17 by CD8+ T cells expressing CD146 (MCAM). Clinical Immunology. 2014; 152:36–47. DOI: 10.1016/j.clim.2014.01.009.
  103. 103. U Srenathan, K Steel, and LS Taams. IL-17+ CD8+ T cells: Differentiation, phenotype and role in inflammatory disease. Immunology Letters. 2016.
  104. 104. A Xin, F Masson, Y Liao, S Preston, T Guan, R Gloury, M Olshansky, J-X Lin, P Li, and TP Speed. A molecular threshold for effector CD8+ T cell differentiation controlled by transcription factors Blimp-1 and T-bet. Nature Immunology. 2016. DOI: 10.1038/ni.3410.
  105. 105. JC Gasson. Molecular physiology of granulocyte-macrophage colony-stimulating factor. Blood. 1991; 77:1131–1145.
  106. 106. I Sonderegger, G Iezzi, R Maier, N Schmitz, M Kurrer, and M Kopf. GM-CSF mediates autoimmunity by enhancing IL-6–dependent Th17 cell development and survival. The Journal of Experimental Medicine. 2008; 205:2281–2294. DOI: 10.1084/jem.20071119.
  107. 107. H Chang, H Hanawa, T Yoshida, M Hayashi, H Liu, L Ding, K Otaki, K Hao, K Yoshida, and K Kato. Alteration of IL-17 related protein expressions in experimental autoimmune myocarditis and inhibition of IL-17 by IL-10-Ig fusion gene transfer. Circulation Journal. 2008; 72:813–819. DOI: 10.1253/circj.72.813.
  108. 108. DM Cortez, MD Feldman, S Mummidi, AJ Valente, B Steffensen, M Vincenti, JL Barnes, and B Chandrasekar. IL-17 stimulates MMP-1 expression in primary human cardiac fibroblasts via p38 MAPK-and ERK1/2-dependent C/EBP-β, NF-κB, and AP-1 activation. American Journal of Physiology-Heart and Circulatory Physiology. 2007; 293:H3356–H3365. DOI: 10.1152/ajpheart.00928.2007.
  109. 109. A Doreau, A Belot, J Bastid, B Riche, M-C Trescol-Biemont, B Ranchin, N Fabien, P Cochat, C Pouteil-Noble, and P Trolliet. Interleukin 17 acts in synergy with B cell–activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus. Nature Immunology. 2009; 10:778–785. DOI: 10.1038/ni.1741.
  110. 110. I Sonderegger, TA Röhn, MO Kurrer, G Iezzi, Y Zou, RA Kastelein, MF Bachmann, and M Kopf. Neutralization of IL-17 by active vaccination inhibits IL-23-dependent autoimmune myocarditis. European Journal of Immunology. 2006; 36:2849–2856.
  111. 111. T Yamashita, T Iwakura, K Matsui, H Kawaguchi, M Obana, A Hayama, M Maeda, Y Izumi, I Komuro, and Y Ohsugi. IL-6-mediated Th17 differentiation through RORγt is essential for the initiation of experimental autoimmune myocarditis. Cardiovascular Research. 2011; 91:640–648. DOI: 10.1093/cvr/cvr148.
  112. 112. J Yuan, A-L Cao, M Yu, Q-W Lin, X Yu, J-H Zhang, M Wang, H-P Guo, and Y-H Liao. Th17 cells facilitate the humoral immune response in patients with acute viral myocarditis. Journal of Clinical Immunology. 2010; 30:226–234. DOI: 10.1007/s10875-009-9355-z.
  113. 113. PM da Matta Guedes, FR Gutierrez, FL Maia, CM Milanezi, GK Silva, WR Pavanelli, and JS Silva. IL-17 produced during Trypanosoma cruzi infection plays a central role in regulating parasite-induced myocarditis. PLoS Neglected Tropical Disease. 2010; 4:e604. DOI: 10.1371/journal.pntd.0000604.
  114. 114. JT Boari, MCA Vesely, DA Bermejo, MC Ramello, CL Montes, H Cejas, A Gruppi, and EVA Rodríguez. IL-17RA signaling reduces inflammation and mortality during Trypanosoma cruzi infection by recruiting suppressive IL-10-producing neutrophils. PLoS Pathogens 2012; 8:e1002658.
  115. 115. PM Da Matta Guedes, FRS Gutierrez, GK Silva, R Dellalibera-Joviliano, GJ Rodrigues, LM Bendhack, A Rassi Jr, A Rassi, A Schmidt, and BC Maciel. Deficient regulatory T cell activity and low frequency of IL-17-producing T cells correlate with the extent of cardiomyopathy in human Chagas' disease. PLoS Neglected Tropical Disease. 2012; 6:e1630. DOI: 10.1371/journal.pntd.0001630.
  116. 116. T Simon, S Taleb, N Danchin, L Laurans, B Rousseau, S Cattan, J-M Montely, O Dubourg, A Tedgui, and S Kotti. Circulating levels of interleukin-17 and cardiovascular outcomes in patients with acute myocardial infarction. European Heart Journal. 2012; 34:570–577. DOI: 10.1093/eurheartj/ehs263.
  117. 117. CG Martinez, D Zamith-Miranda, MG da Silva, KC Ribeiro, IT Brandão, CL Silva, BL Diaz, M Bellio, PM Persechini, and E Kurtenbach. P2× 7 purinergic signaling in dilated cardiomyopathy induced by auto-immunity against muscarinic M2 receptors: autoantibody levels, heart functionality and cytokine expression. Scientific reports. 2015; 5.
  118. 118. JR Schoenborn and CB Wilson. Regulation of interferon-γ during innate and adaptive immune responses. Advances in immunology. 2007; 96:41–101.
  119. 119. O Meyer. Interferons and autoimmune disorders. Joint Bone Spine. 2009; 76:464–473. DOI: 10.1016/j.jbspin.2009.03.012.
  120. 120. PS de Araújo-Souza, SC Hanschke, and JP Viola. Epigenetic control of interferon-gamma expression in CD8 T cells. Journal of Immunology Research. 2015; 2015:1–7. DOI: 10.1155/2015/849573.
  121. 121. SJ Szabo, BM Sullivan, SL Peng, and LH Glimcher. Molecular mechanisms regulating Th1 immune responses. Annual Review of Immunology. 2003; 21:713–758. DOI: 10.1146/annurev.immunol.21.120601.140942.
  122. 122. LK Teixeira, BP Fonseca, A Vieira-de-Abreu, BA Barboza, BK Robbs, PT Bozza, and JP Viola. IFN-γ production by CD8+ T cells depends on NFAT1 transcription factor and regulates Th differentiation. The Journal of Immunology. 2005; 175:5931–5939. DOI: 10.4049/​jimmunol.175.9.5931.
  123. 123. L Baudino, SA da Silveira, M Nakata, and S Izui. Molecular and cellular basis for pathogenicity of autoantibodies: lessons from murine monoclonal autoantibodies. Springer Seminars in Immunopathology. 2006; 28:175–184. DOI: 10.1007/s00281-006-0037-0.
  124. 124. X Hu and LB Ivashkiv. Cross-regulation of signaling pathways by interferon-γ: implications for immune responses and autoimmune diseases. Immunity. 2009; 31:539–550. DOI: 10.1016/j.immuni.2009.09.002.
  125. 125. D Bending, H De La Peña, M Veldhoen, JM Phillips, C Uyttenhove, B Stockinger, and A Cooke. Highly purified Th17 cells from BDC2. 5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. The Journal of Clinical Investigation. 2009; 119:565–572. DOI: 10.1172/JCI37865.
  126. 126. K Boniface, WM Blumenschein, K Brovont-Porth, MJ McGeachy, B Basham, B Desai, R Pierce, TK McClanahan, S Sadekova, and R de Waal Malefyt. Human Th17 cells comprise heterogeneous subsets including IFN-γ-producing cells with distinct properties from the Th1 lineage. The Journal of Immunology. 2010; 185:679–687. DOI: 10.4049/jimmunol.1000366.
  127. 127. R Baccala, DH Kono, and AN Theofilopoulos. Interferons as pathogenic effectors in autoimmunity. Immunological Reviews. 2005; 204:9–26. DOI: 10.1111/j.0105-2896.2005.00252.x.
  128. 128. SP Levick and PH Goldspink. Could interferon-gamma be a therapeutic target for treating heart failure? Heart Failure Reviews. 2014; 19:227–236. DOI: 10.1007/s10741-013-9393-8.
  129. 129. M Afanasyeva, D Georgakopoulos, DF Belardi, D Bedja, D Fairweather, Y Wang, Z Kaya, KL Gabrielson, ER Rodriguez, and P Caturegli. Impaired up-regulation of CD25 on CD4+ T cells in IFN-γ knockout mice is associated with progression of myocarditis to heart failure. Proceedings of the National Academy of Sciences of the United States of America. 2005; 102:180–185. DOI: 10.1073/pnas.0408241102.
  130. 130. M Afanasyeva, Y Wang, Z Kaya, S Park, MJ Zilliox, BH Schofield, SL Hill, and NR Rose. Experimental autoimmune myocarditis in A/J mice is an interleukin-4-dependent disease with a Th2 phenotype. The American Journal of Pathology. 2001; 159:193–203. DOI: 10.1016/S0002-9440(10)61685-9.
  131. 131. JG Barin, GC Baldeviano, MV Talor, L Wu, S Ong, D Fairweather, D Bedja, NR Stickel, JA Fontes, and AB Cardamone. Fatal Eosinophilic Myocarditis Develops in the Absence of IFN-γ and IL-17A. The Journal of Immunology. 2013; 191:4038–4047. DOI: 10.4049/jimmunol.1301282.
  132. 132. G Kania, S Siegert, S Behnke, R Prados-Rosales, A Casadevall, TF Lüscher, SA Luther, M Kopf, U Eriksson, and P Blyszczuk. Innate signaling promotes formation of regulatory nitric oxide-producing dendritic cells limiting T-cell expansion in experimental autoimmune myocarditis. Circulation. 2013; 127:2285–2294. DOI: 10.1161/CIRCULATIONAHA.112.000434.
  133. 133. A Furrer, MO Hottiger, and A Valaperti. Absent in melanoma 2 (AIM2) limits pro-inflammatory cytokine transcription in cardiomyocytes by inhibiting STAT1 phosphorylation. Molecular Immunology. 2016; 74:47–58. DOI: 10.1016/j.molimm.2016.04.009.
  134. 134. CM Cascabulho, DG Beghini, M Meuser-Batista, C Penido, and A Henriques-Pons. Chemotaxis and immunoregulatory function of cardiac γδ T cells in dystrophin-deficient mice. The Journal of Immunology. 2016:1600335. DOI: 10.4049/jimmunol.1600335.
  135. 135. C Massilamany, A Gangaplara, RH Basavalingappa, RA Rajasekaran, V Khalilzad-Sharghi, Z Han, S Othman, D Steffen, and J Reddy. Localization of CD8 T cell epitope within cardiac myosin heavy chain-α 334–352 that induces autoimmune myocarditis in A/J mice. International Journal of Cardiology. 2016; 202:311–321. DOI: 10.1016/j.ijcard.2015.09.016.
  136. 136. P Blyszczuk, C Berthonneche, S Behnke, M Glönkler, H Moch, T Pedrazzini, TF Lüscher, U Eriksson, and G Kania. Nitric oxide synthase 2 is required for conversion of pro-fibrogenic inflammatory CD133+ progenitors into F4/80+ macrophages in experimental autoimmune myocarditis. Cardiovascular Research. 2013; 97:219–229. DOI: 10.1093/cvr/cvs317.
  137. 137. S Ong, DL Ligons, JG Barin, L Wu, MV Talor, N Diny, JA Fontes, E Gebremariam, DA Kass, and NR Rose. Natural killer cells limit cardiac inflammation and fibrosis by halting eosinophil infiltration. The American Journal of Pathology. 2015; 185:847–861. DOI: 10.1016/j.ajpath.2014.11.023.
  138. 138. NL Diny, X Hou, JG Barin, G Chen, MV Talor, J Schaub, SD Russell, K Klingel, NR Rose, and D Čiháková. Macrophages and cardiac fibroblasts are the main producers of eotaxins and regulate eosinophil trafficking to the heart. European Journal of Immunology. 2016. DOI: 10.1002/eji.201646557.
  139. 139. T Weinberger and C Schulz. Myocardial infarction: a critical role of macrophages in cardiac remodeling. Frontiers in Physiology. 2015; 6:107. DOI: 10.3389/fphys.2015.00107.
  140. 140. M Nahrendorf and FK Swirski. Monocyte and macrophage heterogeneity in the heart. Circulation Research. 2013; 112:1624–1633. DOI: 10.1161/CIRCRESAHA.113.300890.
  141. 141. G De Couto, W Liu, E Tseliou, B Sun, N Makkar, H Kanazawa, M Arditi, and E Marbán. Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction. The Journal of Clinical Investigation. 2015; 125:3147–3162. DOI: 10.1172/JCI81321.
  142. 142. O Zimmermann, JM Homann, A Bangert, A-M Müller, G Hristov, S Goeser, JM Wiehe, S Zittrich, W Rottbauer, and J Torzewski. Successful use of mRNA-nucleofection for overexpression of interleukin-10 in murine monocytes/macrophages for anti-inflammatory therapy in a murine model of autoimmune myocarditis. Journal of the American Heart Association. 2012; 1:e003293. DOI: 10.1161/JAHA.112.003293.
  143. 143. D Cihakova, JG Barin, M Afanasyeva, M Kimura, D Fairweather, M Berg, MV Talor, GC Baldeviano, S Frisancho, and K Gabrielson. Interleukin-13 protects against experimental autoimmune myocarditis by regulating macrophage differentiation. The American Journal of Pathology. 2008; 172:1195–1208. DOI: 10.2353/ajpath.2008.070207.
  144. 144. S Gao, J Zhou, N Liu, L Wang, Q Gao, Y Wu, Q Zhao, P Liu, S Wang, and Y Liu. Curcumin induces M2 macrophage polarization by secretion IL-4 and/or IL-13. Journal of Molecular and Cellular Cardiology. 2015; 85:131–139. DOI: 10.1016/j.yjmcc.2015.04.025.
  145. 145. Z Su, P Zhang, Y Yu, H Lu, Y Liu, P Ni, X Su, D Wang, Y Liu, and J Wang. HMGB1 Facilitated macrophage reprogramming towards a proinflammatory M1-like phenotype in experimental autoimmune myocarditis development. Scientific Reports. 2016; 6. DOI: 10.1038/srep21884.

Written By

Eleonora Kurtenbach and Camila Guerra Martinez

Submitted: 27 April 2016 Reviewed: 18 November 2016 Published: 22 March 2017