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Open access peer-reviewed chapter

Macrophage Polarization in Viral Infectious Diseases: Confrontation with the Reality

Written By

Perla Abou Atmeh, Soraya Mezouar and Jean-Louis Mège

Submitted: 01 April 2022 Reviewed: 27 June 2022 Published: 19 July 2022

DOI: 10.5772/intechopen.106083

Macrophages IntechOpen
Macrophages Celebrating 140 Years of Discovery Edited by Vijay Kumar

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Macrophages - Celebrating 140 Years of Discovery

Edited by Vijay Kumar

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Abstract

The role of macrophages in viral infections is well documented. Their activation status also called macrophage polarization categorized by the dichotomy of M1 and M2 phenotype remained poorly investigated. Recent studies have shown the complexity of macrophage polarization in response to viral infection and the limits of its use in infected individuals. The aim of this chapter is to reappraise the concept of macrophage polarization in viral infectious diseases, which are more complicated than the models of macrophage-virus interaction. If this concept has been largely used to describe activation status of myeloid cells in experimental conditions, it has to be assessed in light of high-throughput technologies at molecular and phenotypic levels. We update knowledge on macrophage polarization in viral infectious diseases with a special attention for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection leading to coronavirus disease (COVID-19). Hence, we propose an overview of the concept of macrophages as targets for therapeutic intervention in viral infectious disease. Finally, we tempted to focus our approach on patient investigation restricting the use of in vitro experiments and animal models to mechanistic questions.

Keywords

  • macrophages
  • myeloid cells
  • polarization
  • viral diseases

1. Introduction

First described in 1882 by Ilya Mechnikov, macrophages or “phagocytes” are distributed widely in the body where they acquire specific tissue identities and functions [1]. Macrophages are key effectors of tissue homeostasis contributing to wound healing and tissue repair. When tissue homeostasis is altered, monocytes are recruited from blood to tissues where they differentiate into macrophages. These latter are critical components of innate and adaptive immunity and contribute to inflammation and host defense.

During infection, macrophages represent the first cells on the battle front. They can act as scavengers by engulfing and destroying pathogens or altered host cells, alert the immune system through the secretion of lipid mediators, cytokines, and chemokine; or present antigens to T lymphocytes [2]. The expression of lectins, scavenger receptors, and immunoglobulin receptors enables macrophage phagocytosis, antibody-dependent cell phagocytosis (ADCP) and cytotoxicity (ADCC) [3]. They are also equipped with pattern recognition receptors (PRRs) that following their stimulation lead to the activation of transcription factors, the release of toxic mediators (reactive oxygen intermediates, proteases, inflammatory molecules) [3]. Because of their ability to promote adaptive immune response to virus via antibody release and CD8 T cell activation, macrophages can contribute to the cure of viral infections.

According to their function in pathological conditions, macrophages are considered as activated or alternatively activated also referred to as M1 and M2 polarization phenotype, respectively. The polarization of macrophages is a concept introduced to describe the features of myeloid cell activation and to classify them in functional categories (Figure 1), according to initially reported polarization of immune response into Th1 and Th2 types [4, 5, 6]. The M1 macrophages are induced by Th1 cytokines such as interferon (IFN)-γ and/or lipopolysaccharide (LPS) and present a pro-inflammatory phenotype. They are characterized by the secretion of inflammatory cytokines including tumor necrosis factor (TNF), interleukin (IL)-1α, IL-1β, IL-6, IL-12, IL-23, and also the expression of several markers including CD80, CD86, and CD68. The M2 macrophages are likely more heterogeneous: they have been classified into four categories, M2a, M2b, M2c, and M2d, depending on the stimulus [7, 8]. As described in Table 1, macrophages stimulated by IL-4 or IL-13 lead to an M2a profile associating the expression of CD206, IL-1 receptor type 2 (IL1-R2) and arginase and the secretion of transforming growth factor (TGF)-β and IL-10. M2b macrophages are induced by immune complexes, Toll-like receptor (TLR) ligands, or IL-1β. This profile is associated with the secretion of inflammatory cytokines (TNF, IL-1β, IL-6), IL-10, and the chemokine CCL1. M2c macrophages are induced by IL-10, TGF-β, or glucocorticoids; they expressed CD163 and CD206 and exhibit anti-inflammatory activity through the secretion of IL-10 and TGF-β. Finally, M2d polarization is initiated by TLRs (TLR2, TLR4, TLR7, and TLR9) or adenosine receptor ligands (A2A) with the secretion of vascular endothelial growth factor (VEGF) supporting pro-angiogenic and pro-tumoral functions [9, 10, 11]. It is becoming evident that these categories of activation states are an over-simplification of the diversity of macrophage activation modes. We have tried to reappraise the concept of macrophage polarization by associating the type of polarization with the agonist [12]. This approach allows to propose several activation profiles with LPS, IFN-γ, or their combination instead of a unique M1 activation state [13, 14]. In clinical situations, it has been shown that tumor-associated macrophages (TAMs) are clearly specialized cell populations in which polarization and functions are related: M1-like and M2-like TAMs have anti-tumoral and pro-tumoral activities, respectively [15]. In other clinical situations including infectious diseases, such functional dichotomy is rarely observed [7], and the functional role of macrophage polarization remains an exception.

Figure 1.

In vitro and in vivo macrophage polarization markers and protein secretion.

StimuliMarker expressionCytokine productionChemokine productionFunctions
M1IFN-γ, LPS, GM-CSF, TNFCD68, CD86, CD80, MHC-II, IL1R, TLR2, TLR4, iNOS, SOCS3, IL-12high/IL-10low, IL-6, TNFTNF, IL-1β, IL-6, IL-12, IL-23CCL10, CCL11, CCL5, CCl8, CCL9, CCL2, CCL3, CCL4

  • Pro-inflammation

  • Microbicidal

  • Tumor resistance

M2aIL-4, IL-13CD163, CD206, MHC-II, TGM2, IL-1R II, scavenger receptors, Arg-1IL-10, TGF-β, IL-1raCCL17, CCL22, CCL24

  • Anti-inflammatory

  • Wound healing

M2bLPS + immune complexe, IL-1 β, immune complexes, TLRsCCL1, CD86, IL-6, IL-10high/IL-12low, TNF, MHC-IIIL-1β, IL-6, IL-10, TNFCCL1

  • Immunoregulation

  • Tumor progression

  • Promoting infection

M2cGlucocorticoids, IL-10, TGF-βCD163, TLR8, TLR1, CD206IL-10, TGF-βCCR2

  • Phagocytosis

  • Immunosuppression

  • Tissue remodeling

M2dIL-6, adenosine, leukocyte inhibitory factor, TLRsVEGFIL-10, TGF-β,
TNF, IL-12		CCL5, CXCL10, CXCL16

  • Angiogenesis

  • Tumor progression

Table 1.

In vitro macrophages polarization sub-types.

IFN: interferon, LPS: polysaccharide; GM-CSF: granulocyte macrophage colony stimulating factor; TLR: Toll like receptor; MHC: major histocompatibility complex; iNOS: inducible nitric oxide; Arg: arginase; TNF: tumor necrosis factor; IL: interleukin; TGF: transforming growth factor; VEGF: vascular endothelial growth factor.

The mechanisms of macrophage polarization have been the object of a broad literature. It appears now that the metabolism of macrophages is different according to their polarization. Hence, M1 macrophages exhibit increased glycolysis and broken tricarboxylic acid (TCA) cycle, leading to the accumulation of succinate and citrate. In contrast, M2 macrophages have intact TCA cycle leading to the generation of adenosine triphosphate (ATP) [16, 17]. It is becoming evident that the polarization of macrophages is determined by transcriptional changes, as shown by using new technologies [4]. In aortic macrophages studied in vivo by scRNA-seq, Chang et al. identified three classes of macrophages: resident-like, inflammatory, and a final group with strong expression of triggering receptor expressed on myeloid cells 2 (TREM2) [18]. Interestingly, M2 markers are found in the inflammatory macrophage population, suggesting that the traditional classification of macrophage polarization does not fully reflect the diversity of the in vivo macrophage populations (Figure 1). Quantitative mass spectrometry imaging has also been proposed to investigate macrophage polarization in situ. It enabled the cartography of functional macrophage population and the visualization of their distribution in normal and pathological tissues [19, 20, 21, 22]. In addition, macrophage polarization requires dynamic and reversible epigenomic marks at enhancers and promoters of signal responsive genes [4]. The epigenetic mechanisms of M2 polarization reveal the role of histone methylation and acetylation. Hence, the overexpression of DNA methyltransferase 3B or the loss of histone deacetylase-3 (HDAC3) promotes M2 phenotype. The histone demethylase JMJD3 (lysine demethylase 6B, KDM6B) is activated by IL-4 and binds M2 genes, leading to repress M1 inflammatory program. In contrast, IFN-γ increases chromatin accessibility [4, 23]. Finally, polarization and functional responses of macrophages are influenced by differential expression of microRNAs: the literature has reported miRs specialized in M1 polarization and miRs increasing M2-like responses [24].

Is the specialization of M1/M2-like macrophages evolutionary conserved? Two ancient molecular mechanisms, inducible nitric oxide synthase 2 (iNOS2) and arginase (Arg), characterize macrophage polarization. If the ability to produce large amounts of nitric oxide in response to microbial agonists, a hallmark of M1 macrophages, has emerged with vertebrates, the Arg pathway is described in both prokaryotes and eukaryotes [25]. The cytosolic and mitochondrial Args are encoded by two genes, and it has been shown that the duplication of Arg gene occurred after the separation of vertebrates and invertebrates [26]. Hence, it is likely that macrophage polarization occurs during early vertebrate evolution [27].

The aim of this chapter is to update the knowledge about macrophage polarization in viral infections with a special focus on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We are deciding to analyze papers reporting infections in humans and to restrict animal models for specific questions. The analysis of the literature reveals the heterogeneous definition of macrophage polarization and the frequently inappropriate use of this concept. It is the reason why the final paragraph will describe how macrophage polarization can be studied in patients (Table 2) and to propose some recommendations for investigating infected patients.

M1 macrophageM2 macrophage
Marker expressionCD68, CD86, CD80CD68, CD86, CD80, CD163, CD206
CytokineTNF, IL-1β, IL-6, IL-12, IL-23, IL-18IL-10, TGF-β, TNF, VEGF, IL-1β
FunctionsPro-inflammatory and anti-tumoralPro- and/or anti-inflammatory

Table 2.

In vivo polarization of macrophage sub-types.

TNF: tumor necrosis factor; IL: interleukin; TGF: transforming growth factor; VEGF: vascular endothelial growth factor.

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2. Viral infectious diseases in humans

As obligate intracellular pathogens, viruses require host cells to replicate. Innate defenses are essentials to block or inhibit cell infection, to eliminate virus from infected cells, and to alert cells the adaptive immunity. This crucial stage is regulated by myeloid cells including, dendritic cells, and mainly by macrophages. The early response is based on [1] the recognition of pathogen-associated molecular patterns (PAMPs) by PRRs, [2] the elimination of foreign agents [3] and the activation of type I and II IFNs, and interferon-stimulated gene (ISG), which have broad-spectrum antiviral activity [28, 29]. Although this defense is effective, a complete cure of the infection requires mounting adaptive immune response that is controlled to prevent immune pathogenicity. Macrophage-mediated immune response can be circumvented or hijacked by the virus to allow its replication and persistence in the host.

The first studies highlighting the interaction between myeloid cells and viruses date back to the end of 1970s [30, 31]. In a general point of view, macrophages polarize into M1 following a contact with viruses, which induces a pro-inflammatory response while the phenotype M2 is often found at late stages of infection [32]. It has been reported that virulent strains of viruses will “bias” the M1 polarization profile of macrophages into M2. In contrast, attenuated viruses lead to an M2 polarization profile M2 [33]. M1-activated macrophages play a key role in the elimination of viruses through several strategies, including the secretion of reactive species [34], secretion of antiviral cytokines [35], or activation of other immune cells such as T cells and natural killers [36, 37]. Hence, some viruses are able to counteract M1 macrophages in order to obtain an environment favorable to their replication. Indeed, some viruses are able to inhibit production of nitric oxide [38, 39, 40, 41] or pro-inflammatory cytokines [42, 43, 44], suppress antigen presentation [45, 46, 47, 48], or simply modulate the signaling pathways associated with polarization by inducing M2 phenotype [8, 49, 50, 51]. We previously addressed the role of macrophage polarization in bacterial infections [7, 52]; the aim of the present talk is to assess the role of macrophage polarization in viral infections by selecting typical viral infections.

2.1 Hepatitis viruses

Five viruses, known as hepatitis A, B (HBV), C (HCV), D, and E, are responsible for the majority of acute and chronic hepatitis. HBV infection is responsible of acute self-resolving disease in adults but not in early life. Hepatic macrophages whatever their origin are involved in host response to HBV. HBV antigen and nucleic acids are detected in monocytes and macrophages from patients with hepatitis. The interaction of HBV with macrophages including hepatic macrophages may affect macrophage polarization by suppressing M1 polarization and promoting M2 polarization [53]. M1-associated cytokines are likely protective as shown by higher risk of HBV reactivation and hepatotoxicity in patients with anti-TNF treatment given for inflammatory diseases [54]. During the progression of HBV-related disease (from mild chronic hepatitis B to decompensated cirrhosis), M2-type monocytes expressing CD163 and CD206 are increased, whereas the frequency of cells expressing M1 markers decreases. Monocytes and Kupffer cells expressing an M2 profile are predicting a poor clinical outcome [55]. The non-protective effect of M2-type polarization is illustrated by the observation that IL-10 gene promoter polymorphisms are associated with HBV progression [44]. The measurement of soluble CD163 and soluble mannose receptor may be a pertinent approach of follow-up of patients with chronic hepatitis. Both markers are released during liver damage and are associated with M2 polarization and fibrosis; their levels are reduced after antiviral treatment [56]. The relationship between chronic evolution of hepatitis B, fibrosis, and infiltration of liver by M2-like macrophages has been demonstrated in a humanized mouse model of infection [57].

HCV is transmitted between adults and is responsible for a high percentage of chronic infections with a major risk of liver cirrhosis and hepatocellular carcinoma [58]. The co-culture of monocyte-derived macrophages with HCV-infected hepatocytes induces M2 surface markers. TGF-β produced by these polarized macrophages activates hepatic stellate cells, leading to fibrosis. However, monocytes and macrophages do not seem completely polarized at the cytokine level [59]. Cell-free virus or exosome-packaged HCV induces the differentiation of monocytes into macrophages with M2 phenotype and non-polarized cytokine production under the control of TLR7/8. Interestingly, TLR7/8 is overexpressed in pro-fibrotic monocytes from chronic HCV-infected patients [60]. It has been also shown that HCV core protein inhibits phagocytosis activity of M1 and M2 macrophages and CD4+ T cell activation induced by M1 macrophages but promotes that induced by M2 macrophages [61]. M1 and M2 macrophages generated from chronic HCV patients lose their phenotypic characteristics, suggesting that chronic HCV infection is rather associated with an impaired polarization than a reprogramming of macrophages [62]. Finally, in biopsies of HCV-infected patients, it has been shown that non-infected cells such as Kupffer cells are a source of IFNs, demonstrating the interplay between hepatic cells [63]. Taken together, these data suggest that HBV and HCV share the ability to interfere with M1-type macrophage polarization, thus accounting for viral persistence, hepatic fibrosis, and evolution to carcinoma.

2.2 Human immunodeficiency virus (HIV)

The permissivity of monocytes and macrophages to HIV depends on their differentiation stage, polarization status, and tissue location [64]. The M1/M2 polarization of macrophages impacts the steps of viral cycle including entry, reverse transcription, transcription, and posttranscription. As the level of inflammatory cytokines is high in the early stage of HIV-1 infection [65, 66], it is likely that M1-like macrophages play a role in HIV infection. The entry of R5 and R5/X4 HIV in M1-like macrophages is decreased because of cytokine-mediated downregulation of CD4 and CCR5. In contrast, M1 cytokines such as TNF increase viral transcription. In M2 macrophages elicited by IL-4/IL-13 and/or IL-10-mediated deactivated macrophages, both entry and replication of HIV-1 are decreased [64]. The implication of TNF in M1 polarization of HIV-infected macrophages is debated [67]. Hence, it is likely that M1 macrophages enable the formation of viral reservoirs early in the disease. At later stages, an M2 shift of macrophages is observed. At the onset of acquired immunodeficiency syndrome (AIDS), deactivated macrophages predominate via enhanced clearance of apoptotic cells, which is known to promote M2-like macrophages [68]. Severe evolution of HIV infection is associated with elevated IL-10 levels, but not IL-4 levels, suggesting that AIDS is characterized by IL-10-mediated M2-like phenotype [69]. These findings have been confirmed in acute and chronic HIV and SIV infections. Hence, at the beginning of the infection, the central nervous system, heart, and blood vessels exhibit M1-like macrophages, whereas M2-like macrophages are observed in later responses [32]. It is likely that CD163+ M2 macrophages play a protective role in SIV-infected macaques through their anti-inflammatory functions [70]. It has been proposed that the persistence of initial activation in patients with chronic infection and successful antiviral therapy is correlated to non-AIDS complications such neurocognitive disorder and cardiovascular dysfunctions [71]. Unfortunately, few markers have been investigated in these studies, and it is likely that more precise data will be necessary to reanalyze the polarization of macrophages in HIV infection [71, 72].

2.3 Flavivirus

Flavivirus is responsible for infections essentially dominated by dengue virus (DENV) and Zika virus (ZIKV). First, DENV infection presents a large spectrum of clinical presentations from moderate symptoms to classical dengue and hemorrhagic dengue. Monocytes and macrophages are involved in the infection pathogenesis. Macrophage-colony-stimulating factor (M-CSF)-differentiated macrophages (M2-like macrophages) are poorly sensitive to DENV infection. In contrast, granulocyte macrophage CSF (GM-CSF)-differentiated macrophages (M1-like macrophages) are highly susceptible to DENV infection with high release of cytokines and activation of NLRP3 inflammasome [73]. Nevertheless, some biomarkers such as soluble CD163, known to be associated with M2 polarization of macrophages, seem predictive of severe dengue [74]. In pediatric dengue patients compared with healthy individuals, the number of M2-like macrophages is increased with decreased number of M1-like macrophages. In dengue patients with bleeding trend, both macrophage subsets are decreased and are associated with decreased platelet count [48]. Second, ZIKV is associated with numerous cases of microcephaly and/or central nervous system malformations. ZIKV infects myeloid cells and has a tropism for placenta including maternal and fetal tissues. It has been shown that ZIKV replicates in both placenta macrophages, also named Hofbauer cells, and trophoblasts [75]. Two lineages of ZIKV, African and Asian, have been described, and it has been shown that they exhibit differences in pathogenicity despite close sequence homology [76, 77]. While the Asian strain of ZIKV elicits an expansion of non-classical monocytes from healthy donors and M2-skewed immunosuppressive program, African strain promotes a M1 program [78].

2.4 Cytomegalovirus (CMV)

Human CMV (hCMV) uses TLR2 and intracytosoplasmic sensors to invade monocytes and macrophages [79]. In monocytes, hCMV stimulates a transcriptomic program in which M1 genes are enriched [80]. On the other hand, a product of hCMV genome, UL111A gene, encodes functional homologs of human IL-10 during both productive and latent phases of CMV infection [81]. In CD14+ monocytes, the viral IL-10 induces M2c phenotype associating increased expression of CD163 and CD14 and downregulation of HLA-DR. The viral IL-10 also upregulates heme oxygenase 1 (HO-1), a driver of phenotype shift to M2 macrophages [82] known to also down-modulate M1-associated cytokines and poorly stimulate CD4+ T cells [83]. We hypothesize that CMV triggers an M1 program in monocytes and that the release of viral or human IL-10 leads bystander monocytes to be reprogrammed toward an M2 phenotype. The polarization of monocytes in response to hCMV is likely necessary for their differentiation into macrophages. Recently, it has been shown that hCMV stimulates the expression of M1 and M2 markers in monocytes and activates PI3K-Akt axis, leading to caspase 3 activation [84]. CMV susceptibility is dependent on polarization of myeloid cells. M1-like macrophages are more resistant to CMV than M2-like macrophages, and it is likely that this resistance is related to the ability of M1-like macrophages to induce IFN-γ production by natural killer (NK) cells [85]. This hypothesis is supported by two other studies. Although hCMV susceptibility is higher in M2-like macrophages, productive and persistent viral infection is observed in both M1- and M2-like macrophages. Infected M1- and M2-like macrophages are efficient in stimulating proliferation of autologous T cells from hCMV-seropositive donors [86]. The susceptibility of M2 macrophages is optimal in the early phase of hCMV infection, whereas, in the late phase, macrophage activation necessary for viral replication is dependent on the activation of mammalian target of rapamycin (mTORC)1 complex, as confirmed with experiments including rapamycin [87].

2.5 Influenza virus

Four influenza virus genera (A, B, C, and D) belonging to orthomyxoviridae are responsible for flu, a seasonal respiratory epidemics, or pandemics, such as the “Great Influenza” pandemics of 1918 [88]. The severity of influenza pneumonia depends on host susceptibility and strain diversity and can lead to acute respiratory distress syndrome and lethality. These latter complications are associated with uncontrolled inflammatory response. Numerous evidences show that macrophages including alveolar macrophages are involved in the pathophysiology of influenza virus infections via a direct viral infection or the overproduction of cytokines. This is emphasized by the observation that over-pathogenic strains of influenza virus productively infect monocytes [89]. Animal models demonstrate that macrophage reprogramming is critical in outcome of influenza virus infections. Hence, GM-CSF protects from mortality and morbidity and redirects responses of alveolar macrophages from M1-like to M-2-like activation. This finding was unexpected because GM-CSF is known as an M1 inducer and depresses arginase, a canonical marker of M2-like status [90]. The inactivation of NOS (nitric oxide synthase) 2 and IFN-γ favors M2 reprogramming and improves outcome of viral infection [91]. In contrast, the treatment of macrophages with baicalin that possesses antiviral properties stimulated an M1 phenotype shift associated with activation of IFN pathway and inhibition of influenza virus replication [92].

The evidences of macrophage polarization in humans infected with influenza virus are scarce. In one study of patients from the 2009 to 2010 pandemics, monocytes have been reported as a marker of severity independently of viral load [93]. Monocytes from patients with severe infection exhibit increased expression of M1 markers and TNF production and a down-modulation of CD163, an M2 marker. Murine models of influenza virus infection also show high proportion of recruited M1 monocytes and decreased number of resident M2 alveolar macrophages, confirming that the severity of influenza virus infection is associated with macrophage reprogramming toward an M1 phenotype [93].

2.6 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

SARS-CoV-2, a strain of the coronavirus family, causes coronavirus disease-2019 (COVID-19) characterized in the most severe cases by an increased production of cytokines including IL-1α, IL-1β, IL-6, IL-7, TNF, type I and II IFN, CCL2, CCL3, and CXCL10 [94, 95]. This cytokine storm was initially observed in influenza syndrome that occurs after systemic infection and immunotherapy [96] before it was extended to describe immune response in COVID-19 patients [97]. To better understand the pathophysiology of this emergent disease, the researchers focused on the response of myeloid cells such as macrophages or dendritic cells. Macrophages are permissive to SARS-CoV-2 infection but no viral replication is observed in vitro [98, 99]. Interestingly, the production of inflammatory cytokines and chemokines is observed after SARS-CoV-2 infection of macrophages but not after infection of monocyte-derived dendritic cells [98, 100]. The release of TNF, IL-1β, IL-10, IFN-α/β, and IL-6 by infected-macrophages leads to type I IFN-immune response, suggesting a protective role against viral infection [100].

The polarization of macrophages in COVID-19 has also been investigated. Alveolar macrophages respond differently to infection depending on their polarization status. After SARS-CoV-2 infection, M1 macrophages are associated with viral spreading, whereas M2 polarization induces virus degradation and infection limitation. Indeed, macrophages from human ACE2 transgenic mice present an increased infection rate after in vitro treatment by IFN-γ or LPS compared with IL-4 treatment [101]. These results are controversial because the SARS-CoV-2 infection of M1 and M2 macrophages from the THP-1 cell line is similar [99]. The gene expression study of lung alveoli from COVID-19 patients reveals different macrophage patterns depending on their polarization profile. The gene expression study of lung alveoli from COVID-19 patients shows that highly inflammatory macrophages are mostly found in patients with severe COVID-19 [102, 103]. Thus, the polarization of macrophages during infection by SARS-CoV-2 is suggested as determining the severity of the disease, even if involved molecular mechanisms remain unexplored to date.

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3. Macrophage polarization and treatment of viral infections

The role of deregulated immune response in pathogenesis of viral infections such as COVID-19 pandemics justifies the use of drugs that target host response and exhibit anti-infective properties. Hence, chloroquine and hydroxychloroquine are known for their antiviral and immunomodulatory effects, which lead to propose these molecules in the treatment of SARS-Cov2 infection [104]. Beyond the debate about the efficiency of chloroquine and hydroxychloroquine, their immunomodulatory properties affect the macrophage polarization. It is established that treatment with chloroquine can reverse the polarization of TAMs from M2 to M1 phenotype in tumor models [105]. Similarly, chloroquine and hydroxychloroquine interfere with LPS-mediated M1 polarization of macrophages [106]. The combination of hydroxychloroquine and azithromycin is interesting since this latter molecule is known to induce M2 macrophage polarization [106, 107]. Ivermectin, a macrocyclic lactone known for its antiparasitic effect, has an anti-inflammatory effect promoting M2 polarization of macrophages without effect on viral load; it has been proposed to limit the inflammation of respiratory tract and to improve COVID-19 outcome [108]. Remdesivir, an adenosine analog, reduces inflammatory gene expression and has been largely used in COVID-19 treatment [109].

As mentioned above, M1 polarization of macrophages is a determining phenotype against viral infections. The artificial induction of macrophage M1 polarization may be an interesting adjuvant to antiviral treatment for non-COVID19 infectious diseases. Baicaline has been proposed to limit influenza virus infection via the M1 polarization of macrophages, thus activating their antiviral function via the IFN signaling pathway [92, 110]. It is important to note that viral infections can lead to hyperactivation of macrophages, leading to an excessive inflammatory response known as macrophage activation syndrome. In this context, anti-inflammatory molecules such as tofacitinib, anti-IL1R, or IL-6R have been clinically tested, particularly for COVID-19 [111, 112].

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4. Conclusion and perspectives

As the first line of defense, macrophages represent key immune cells against viral infections. In general, the antiviral response is mediated by a pro-inflammatory response of polarized M1 macrophages. Some viruses are able to counteract the antiviral response of macrophages by modulating their polarization by switching the M1 phenotype to M2 phenotype. It should also be noted that viruses such as influenza and SARS-CoV-2 are capable of modulating an M1 over-polarization of macrophages responsible for severe diseases. Interestingly, modulation of macrophage polarization has been investigated as a therapeutic strategy. However, the in vivo polarization profile remains more intricate compared with in vitro situations. This can be explained by the techniques classically used for investigating macrophage polarization (gene or protein expression) whose limitation is that the observed signals result from a mixture of diverse cells. Hopes for quantitative mass spectrometry imaging as a tissue-level investigative tool remain unanswered to date. Thus, clarifying the tools for investigating macrophage polarization in clinical settings and the associated molecular mechanisms are key steps in the development of therapies in viral infections.

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Acknowledgments

Soraya Mezouar was supported by a “Fondation pour la Recherche Médicale” postdoctoral fellowship (reference: SPF20151234951). This work was supported by the French Government under the “Investissements d’avenir” (Investments for the future) program managed by the “Agence Nationale de la Recherche” (reference: 10-IAHU-03).

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Author contributions

P.A.A, S.M., and J.L.M. conceived and wrote the manuscript.

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Declaration of interest

The authors declare no competing interests.

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Written By

Perla Abou Atmeh, Soraya Mezouar and Jean-Louis Mège

Submitted: 01 April 2022 Reviewed: 27 June 2022 Published: 19 July 2022

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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