Abstract
Leprosy is a chronic infectious disease caused by the intracellular pathogen Mycobacterium leprae. The disease may present different clinical forms depending on the immunological status of the host. M. leprae may infect macrophages and Schwann cells, and recent studies have demonstrated that macrophages are fundamental cells for determining the outcome of the disease. Skin lesions from patients with the paucibacillary form of the disease present a predominance of macrophages with a pro-inflammatory phenotype (M1), whereas skin lesions of multibacillary patients present a predominance of anti-inflammatory macrophages (M2). More recently, it was shown that autophagy is responsible for the control of bacillary load in paucibacillary macrophages and that the blockade of autophagy is involved in the onset of acute inflammatory reactional episodes in multibacillary cells. So, strategies that aim to induce autophagy in infected macrophages are promising not only to improve the efficacy of multidrug therapy (MDT) but also to avoid the occurrence of reactional episodes that are responsible for the disabilities observed in leprosy patients.
Keywords
- macrophages
- leprosy
- innate immunity
- scavenger receptors
- autophagy
1. Introduction
Macrophages are highly plastic and heterogeneous in several aspects, presenting a spectrum of distinct phenotypes according to the microenvironment [1, 2, 3]. During mycobacterial infection, its membrane components have the ability to induce polarization and interaction with this type of cell [4]. The cell wall of
Studies have demonstrated the ability of
The persistence of
2. Macrophage polarization and M. leprae infection
Macrophages are specialized cell types present in most mammalian tissue. Recently, many studies have been highlighting the “general” and “tissue-specific” functions of macrophages, including their roles in systemic metabolism, fibrosis, development, cancer, and tissue homeostasis [27]. However, these cells are best known for their role in the innate immunity, which was first addressed by Ilya Metchnikoff in 1884 in his work describing the “phagocytes” [28]. Several subsets of macrophages were described in different pathological conditions and tissues of humans and mice based on their phenotype and biological functions [1, 29, 30, 31]. Despite their high plasticity, macrophages are classically described in two main functionally distinct phenotypes—classically activated or inflammatory macrophages (M1) and alternatively activated or healing macrophages (M2)—reflecting the T helper type (Th) 1 and Th2 response profiles [2, 3, 30].
In summary, M1 macrophages are induced by lipopolysaccharide and IFN-γ in a pro-inflammatory environment promoting a microbicidal and inflammatory phenotype, while polarization to M2 macrophages, induced in response to IL-4 (M2a), immune complexes (M2b) or IL-13 and IL-10 (M2c), is rather anti-inflammatory and associated with healing and tumor progression. In addition, granulocyte and macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) induce the differentiation of macrophages into, respectively, M1 and M2 phenotypes [2, 3, 32, 33]. Previously, it was demonstrated that macrophages differentiated with GM-CSF or M-CSF were able to phagocytose
In 2016, the protein jagged 1 (JAG1) was identified as a potential regulator of macrophage polarization in leprosy [35]. While unstimulated endothelial cells lead to M2 macrophage polarization, in the presence of IFN-γ, endothelial cells induce the differentiation to M1 macrophages. JAG1 is preferentially expressed in the vascular endothelium in skin lesions of paucibacillary tuberculoid patients, stimulating the differentiation of M1 antimicrobial macrophages by the IFN-γ-JAG1 axis [35].
Due to increased systemic pro-inflammatory mediators, a higher frequency of apoptosis was described in paucibacillary tuberculoid patients [36]. Curiously, the phagocytosis of apoptotic cells in the presence of
Analysis of paucibacillary tuberculoid and reversal reaction (an acute inflammatory clinical condition associated with increased levels of IFN-γ in leprosy patients) patients’ skin lesions demonstrated that macrophage subtypes with microbicidal and homeostatic functions are spatially distributed in tuberculoid granulomas according to the specific microenvironments [38]. The center of the tuberculoid granulomas appears to be populated by pro-inflammatory CD68+ CD163− M1 macrophages, responsible for containing the infection, while the periphery is composed of anti-inflammatory CD68+ CD163+ M2 macrophages, tasked with limiting tissue damage caused by the M1 macrophage antimicrobial activity [39]. Accordingly, Montoya and colleagues [22] proposed two different macrophage functional programs for the polar clinical forms of leprosy. They suggested that in tuberculoid paucibacillary patients, IL-15 induces the vitamin D-mediated antimicrobial program in the macrophages, resulting in killing of the mycobacteria, while in multibacillary lepromatous patients, the higher levels of IL-10 would induce the phagocytic pathway by increasing the expression of CD209 and scavenger receptors as CD163 in the macrophage cell surface, resulting in phagocytosis of
Several studies demonstrated the predominance of M2 markers like CD68, CD209, CD163, SRA-I, HO-1, arginase-1, IL-10, IL-13, TGF-β, and basic fibroblast growth factor in multibacillary lepromatous patients’ skin lesion macrophages [16, 22, 37, 42, 43, 44]. In the same way, CD163, the hemoglobin (Hb) scavenger receptor, might contribute to the polarization of multibacillary lepromatous macrophages to an anti-inflammatory profile by increasing the expression of indoleamine 2,3-dioxygenase (IDO) and IL-10, in addition to increasing the internalization of
A different subset of macrophages, known as M4, was described in skin lesions from lepromatous patients. M4 macrophages in lepromatous skin lesions were described as CD68-positive cells that express myeloid-related protein 8 (MRP8) and matrix metalloproteinase (MMP)-7 [48]. This particular subset of macrophages is differentiated with the platelet chemokine CXCL4 and is mostly related to the formation of foamy cells present on atherosclerotic lesions due to increased expression of LDL receptors. Macrophages differentiated with this chemokine present a functionally distinct phenotype characterized by increased expression of CD206, CD68, IL-6, TNF, MRP8, MMP7, and MMP12, suppressed phagocytic capacity, and the complete lack of CD163 accompanied by the inability to induce HO-1 in response to Hb-Hp complexes, which is irreversible even after removal of CXCL4 and stimulation with M-CSF or IL-10 [32, 48, 49]. Expression of IL-6 and TNF, cytokines associated with the promotion of microbicidal M1 macrophages responses, was increased on skin lesions of paucibacillary tuberculoid patients [48]. Additionally, in vitro exposure to
3. The role of macrophages in the immune response to M. leprae
One of the most crucial steps in a human innate immune response is how the host cells recognize a microbial pathogen. The TLR family has a vital role in the mycobacterial recognition and subsequently induction of antimicrobial defenses and adaptive immune response [51]. Recognition of
The activation of PRR can induce the antimicrobial autophagy pathway, a biological process regulated by multiple specialized proteins known as autophagy-related proteins (ATG), and can be started in response to various cellular stresses and signals such as nutrient withdrawal, growth factor deprivation, and cytokine stimulation and also by pathogen infection [47]. In addition to the role of autophagy in the elimination of potentially toxic protein aggregates and in the prevention of neurodegeneration [56], autophagy plays a key role in the host’s response to mycobacterial infection, because it is able to reverse the blockade of phagosome maturation, inhibiting the intracellular survival of the pathogen [57]. It has been shown that autophagy is an important innate mechanism associated with leprosy immunopathogenesis [58]. Recently, it was demonstrated that autophagy enhances the ability of
As mentioned earlier, the paucibacillary tuberculoid skin macrophages activate the vitamin D pathway and produce antimicrobial peptides that could be involved in autophagy induction. In addition, Silva and colleagues [58] demonstrated that autophagy is differentially regulated between leprosy polar forms. In paucibacillary tuberculoid skin lesion macrophages, IFN-γ/beclin 1-induced autophagy contributes for
Galectins are a family of β-galactoside-binding cytosolic lectins that monitors endosomal and lysosomal integrity. These danger receptors can detect bacterial invasion by detecting unusual exposure of glycans to the cytosol and activate antibacterial autophagy [66, 67, 68]. Immunohistochemistry analysis of leprosy lesions revealed a higher expression of galectin-3 protein on lepromatous macrophages than tuberculoid cells. The increased galectin-3 expression in lepromatous cells was associated with the reduction of dendritic cell differentiation and T-cell antigen presentation [69]. Interestingly, galectin-3 was associated with both bacterial control and survival, as well as autophagy activation and inhibition [66, 68], whereas galectin-8 was related to antibacterial autophagy activation [67, 68]. The underlying cellular mechanisms of target
Although the innate activation of macrophages orchestrates antimicrobial responses that contribute to host defense against intracellular pathogens such as
4. Macrophage autophagy as a target for the control of the disease
Leprosy remains a major global problem. Early detection of cases and immediate treatment with multidrug therapy (MDT) remain the main intervention strategies [70]. Despite the effectiveness of MDT in controlling the polar forms of the disease, limitations in terms of persistent activity in paucibacillary patients, in combination with the persistence of live and/or dead bacilli in multibacillary patients, have been observed, which has repercussions on the frequency of relapses and reactional episodes after treatment [71, 72]. Recent studies have demonstrated that autophagy is an important molecular mechanism for controlling the viability of mycobacteria in the host cell and of the bacillary load in patients with leprosy [58, 59, 60]. Autophagy can be induced by oxidative stress or by an infectious agent and is closely associated with the immune response and host defense [73, 74]. In addition to its homeostatic role, the autophagic degradation pathway is involved in several human diseases, including metabolic disorders, neurodegenerative diseases, cancer, and infectious diseases. Given these observations, pharmacological approaches to regulate positively or negatively this pathway are receiving considerable attention. For example, positive regulation of autophagy may be of therapeutic benefit in certain neurodegenerative diseases (e.g., Huntington’s disease), while inhibition of autophagy is being investigated as a strategy for treatment of some cancers [75, 76]. The molecular regulators interconnecting autophagy and apoptosis, including BCL2, BCL2-associated X protein (BAX), and beclin 1, have been suggested to act as switching points that are critical for the outcome of tumor cells, and lysosomes have been reported to initiate the cell death pathway in autophagic cells [77, 78]. Regarding leprosy, it was observed that in skin cells of patients with the lepromatous form of the disease there is a blockade of the autophagic flux that can be attributed to the increased expression of the antiapoptotic protein BCL2, which inhibits autophagy mediated by beclin 1 [58]. Blockade of the autophagic machinery in lepromatous cells may contribute to the persistence of mycobacteria in host cells. Genetic studies on leprosy have shown that several polymorphisms in genes associated with the control of autophagic pathways such as IFN, immunity-related GTPase family M protein (IRGM), NOD, and TLR play a prominent role in susceptibility to the disease, thus demonstrating the importance of understanding, inducing, and controlling this biological process in leprosy [79, 80, 81, 82, 83, 84, 85].
When the initial studies aiming at induction of autophagy were conducted, the only known drug capable of inducing autophagy chronically was rapamycin. However, the adverse effects of rapamycin (which were not associated with the induction of autophagy) made this drug unattractive to use. Several drugs and nutritional supplements can induce autophagy, such as verapamil, statins, metformin, resveratrol, vitamin D, and omega 3 [86]. Although it is not known whether these agents exert their beneficial clinical effects through the induction of autophagy or other pathways, there is a considerable overlap between diseases occurring in an environment of poor autophagy and diseases that respond to drugs that may induce autophagy. With regard to infectious diseases, there are limited data on the usefulness of autophagy-inducing pharmaceutical agents as potential therapeutics against human pathogens. Drug screening studies that aim to identify molecules with pro-autophagic effects have been performed, and promising results demonstrated a pro-autophagic effect of drugs capable of inhibiting the growth of
Activation of autophagy by verapamil has been demonstrated by several groups. Initial studies evaluating the effect of verapamil and its analogs on macrophages infected with
Together, these data show the importance of autophagy in the pathogenesis of leprosy, contributing to a better understanding of the mechanisms of mycobacterial control associated with the lepromatous and tuberculoid leprosy poles, which may lead to the establishment of new targets and therapeutic strategies to control leprosy. Moreover, the identification of autophagy as an important factor during the establishment of resistant and susceptible forms of the disease opens the door for the development of new therapeutic strategies of disease control through the modulation of autophagy.
5. Conclusion
Considering the aspects observed during the course of this chapter, macrophages have a crucial role in inducing the immune response to
Acknowledgments
The authors of this chapter have research support from the Brazilian National Council for Scientific and Technological Development (CNPq), the Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (FAPERJ), and the Brazilian Coordination for the Improvement of Higher Education Personnel (CAPES).
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