Open access peer-reviewed chapter

Shifting Macrophage Phenotypes in Leishmaniasis

Written By

Natália S. Vellozo, Flávia L. Ribeiro-Gomes and Marcela F. Lopes

Submitted: 05 February 2022 Reviewed: 26 May 2022 Published: 16 September 2022

DOI: 10.5772/intechopen.105571

From the Edited Volume

Macrophages - Celebrating 140 Years of Discovery

Edited by Vijay Kumar

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Abstract

Macrophage phenotypes, such as macrophage (M) 1 (classically activated macrophage) and M2 (alternatively activated macrophage), determine the macrophage role as an effector immune cell or as a permissive host for the intracellular pathogenic protozoan Leishmania spp. Leishmania parasites and the host immune system shape macrophage phenotypes, which in turn can help parasite control or promote infection. Here, we discussed how shifting macrophage phenotypes might change disease outcome in leishmaniasis, by addressing: (1) macrophage phenotypes in leishmaniasis; (2) the functional phenotypes of resident and inflammatory macrophages; (3) the interplay with neutrophils modulates macrophage function; (4) the crosstalk with T cells shapes macrophage phenotypes; and (5) potential therapeutic tools to skew macrophage phenotypes and disease outcomes.

Keywords

  • macrophage phenotypes
  • M1 and M2 macrophages
  • neutrophils
  • T cells
  • potential therapeutic tools
  • Leishmania

1. Introduction

Leishmaniasis is a neglected tropical disease caused by more than 20 different species of protozoan parasites belonging to the genus Leishmania [1]. About 1 billion people live in endemic areas of leishmaniasis in 92 countries. Currently, 11 million people are infected, with an estimated 1.5 million new cases each year [2]. The clinical manifestations of the disease range from localized skin lesions to disseminated or visceral forms [1], depending on the Leishmania species, host features, and the type and magnitude of the immune responses [3]. Cutaneous leishmaniasis (CL) is the most common clinical manifestation, with 700,000 to 1 million new cases worldwide annually. Other disease forms include mucocutaneous leishmaniasis (MCL), diffuse cutaneous leishmaniasis (DCL), and the aggressive and more lethal form of the disease, visceral leishmaniasis (VL), which can progress to post-kala-azar dermal leishmaniasis (PKDL) [4, 5]. Leishmania species responsible for the cutaneous clinical forms include the Leishmania mexicana complex (L. mexicana, L. amazonensis, and L. venezuelensis), the Leishmania Viannia complex [L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, and L. (V.) peruviana], Leishmania tropica, Leishmania major,and Leishmania aethiopica. Some of these species are also responsible for the MCL and DCL forms. Leishmania donovani, Leishmania infantum, and Leishmania chagasi mainly cause VL and PKDL [5].

Leishmania spp. parasites can induce distinct immune responses, depending on species-specific parasite components and/or the type and strength of the host immunity [3]. Early upon infection, the interactions between Leishmania parasites and neutrophils, dendritic cells (DCs), and macrophages shape the type of acquired immune response, crucial for disease progression or control of infection [6, 7] (Figure 1). Macrophages are permissive host cells for Leishmania parasites, but once activated, they can destroy intracellular parasites. Therefore, macrophages play a key role in innate immunity and in the development of acquired immune response, ultimately leading to the resolution of infection or disease progression.

Figure 1.

Macrophages play a key role in immunity to Leishmania spp. Leishmania parasites infect (a) macrophages, (b) neutrophils, (c) monocytes, and (d) dendritic cells (DCs). (a) Dermal-resident M2 are parasite-permissive host cells, maintained by eosinophil-derived IL-4. (b) Neutrophils interact with infected macrophages to induce either tumor necrosis factor (TNF)-α-mediated parasite killing or TGF-β-promoted infection in different mouse strains. Infected “trojan horses” neutrophils transfer parasites to macrophages and DC upon TAM-receptor-mediated efferocytosis. (c) Infected monocytes either kill parasites through ROS and NO production or turn into parasite-permissive Arg-1+ host cells. Monocytes can also differentiate into macrophage and DC. (d) Infected DCs secrete IL-12 and induce interferon-γ-(IFN-γ) producing Th1 cells that activate M1 to kill parasites. Otherwise, DCs that interact with apoptotic neutrophils inhibit T cell activation. Upon interaction with apoptotic/infected neutrophils, macrophages became infected and induce IL-4-producing Th2 cells, which alternatively activate (M2) macrophage to perpetuate infection and inhibit M1-mediated parasite killing.

Macrophages can assume a plethora of functional phenotypes, ranging from M1 to M2, depending on the signals provided by the environment, including Th1 and Th2 cytokines [8, 9, 10]. Whereas M1 designates macrophages that eliminate intracellular parasites, at the M2 opposite pole, macrophages can sustain Leishmaniareplication [10]. However, an unbalanced M1 response may lead to exacerbated inflammation and tissue damage [10, 11]. The balance between the microbicidal M1 responses and M2/regulatory macrophages might be the key to successfully overcoming leishmaniasis. Here, we will discuss how the interactions between Leishmania parasites and the host immune system affect macrophage phenotypes and how these phenotypical changes determine disease outcomes in leishmaniasis. A better understanding of factors involved in the development of macrophage phenotypes during Leishmania infection is important to design therapeutic strategies capable of modulating the pathogenesis of disease.

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2. Macrophage phenotypes in leishmaniasis

Although different species of Leishmania trigger distinct immune responses [12, 13, 14], seminal work catalyzed advances, by employing the experimental L. major model of CL, where C57BL/6 (B6) and BALB/c mice are, respectively, resistant and susceptible to infection. In B6 mice, the Th1 cytokine interferon-γ (IFN-γ) induces classically activated macrophages (M1), which express induced nitric oxide synthase (iNOS) and produce NO (nitric oxide) to kill L. major parasites [8, 15, 16, 17]. By contrast, in BALB/c mice, the Th2 cytokine IL-4 [18] induces alternative activation of macrophages (M2), characterized by arginase-1 expression and pro-infection activity [19]. While the Th1 versus Th2 paradigm explains relatively well macrophage phenotypes in murine L. major infection, a more complex picture emerges from infections with different Leishmania spp [20, 21]. Whereas L. major-infected macrophages rely on T cell cytokines to control infection, L. braziliensis directly activates macrophages for parasite killing [22]. Moreover, despite the intrinsic phenotypical differences in B6 and BALB/c macrophages [8], both mouse strains are resistant to L. braziliensis infection [23]. Likewise, L. braziliensis, but not L. major parasites, induces M1 phenotype in inflammatory macrophages from both B6 and BALB/c mice [24]. In human peripheral blood mononuclear cells (PBMCs), L. braziliensis induces CXCL10 proinflammatory cytokine, a M1 feature [25]. Furthermore, ML caused by L. braziliensis and L. panamensis is characterized by Th1-type responses that produce pro-inflammatory cytokines and the presence of macrophages with low parasitism [26]. Accordingly, the induction of M1 macrophages in vivo may underlie host resistance following L. mexicana and L. braziliensis infection [27].

Recently, M1 and M2 macrophages were analyzed in skin biopsies from patients infected with several Leishmania spp. M1 macrophages were detected in L. chagasi infection, whereas more M2 macrophages were observed in patients infected with L. amazonensis than in L. braziliensis lesions [14]. In agreement with these findings, DCL caused by L. (L.) amazonensis is characterized by a Th2-type immune response with production of anti-inflammatory cytokines associated with highly parasitized macrophages [26, 28, 29]. Moreover, the enhanced survival of intracellular parasites has been correlated with the M2 phenotype [10, 30, 31, 32]. Likewise, in PKDL caused by L. donovani, there is a decrease in the production of radical oxygen species (ROS) and NO by macrophages that express CD206 and arginase-1, indicating that M2 macrophages are deleterious [33].

Other studies also suggest that preferential infection in M2 cells plays a role in the severity of CL, DCL [30, 31, 34, 35], and VL [36, 37, 38, 39, 40]. Intrinsic characteristics of the parasites that result in enhanced survival within human macrophages, such as resistance to NO [41] or, otherwise, increased expression of IL-4 and arginase-1 [42] have been associated with defective parasite control, larger lesions, and longer disease duration. The results discussed here suggest that the polarization of macrophages to M1 or M2 phenotypes following infection with different Leishmania species might underlie the disease outcomes.

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3. The phenotypes of resident and inflammatory macrophages

Tissue-resident macrophages maintain homeostasis, carry out immunological surveillance, and act in the initiation and resolution of inflammation, depending on environmental factors that induce activation and gene expression [43]. In addition, tissue-resident M2 macrophages promote tissue repair [43, 44].

Dermal-resident M2 macrophages are preferentially infected by L. major Seidman (LmSd) strain, isolated from a patient with nonhealing skin lesions. The eosinophil cytokines IL-4 and IL-10 maintain the M2 phenotype [45], even in the Th1-biased B6 mice. Furthermore, dermal-resident M2 macrophages, characterized by high expression of arginase-1 and mannose receptor, are not replaced by inflammatory macrophages after infection [31]. Remarkably, M2 macrophages use mannose receptor, a M2 hallmark, to internalize Leishmania parasites [31]. Dermal-resident M2 macrophages were also the predominant cell type infected with the L. major Ryan strain at 1 hour and 24 hours after sand fly bite [46]. The preferential parasite growth in resident M2 macrophages may correlate with oxidative deficiency compared to that of inflammatory macrophages [19, 47]. Likewise, liver-resident Kupffer cells have defective ROS generation after infection with L. donovani in vivo or in vitro compared to monocyte-derived macrophages [48, 49].

After recognition of the pathogen, resident macrophages drive neutrophil and monocyte influx from the blood. The importance of resident macrophages in the initiation of inflammatory responses is evident after their depletion, which affects the production of chemokines and, consequently, the influx of neutrophils and monocytes [50]. The number of recruited cells exceeded the number of resident cells by 500-fold 14 days after B6 mice infection with L. amazonensis [51]. Similarly, F4/80hi peritoneal macrophages were replaced by CD11b+Ly6C+F4/80int monocytes 1–2 days after peritoneal infection with L. major or L. braziliensis [24].

At the beginning of L. major infection, parasites are observed inside immature monocytes recruited to the site of infection both in susceptible BALB/c and resistant B6 mice [52]. Over the first few days, inflammatory monocytes become the main infected cells [53]. However, as the infection progresses, monocytes eliminate the parasites while they differentiate into macrophages [52, 54]. In B6 mice, inflammatory monocytes recruited at 4 h post intraperitoneal infection with L. major efficiently kill parasites via ROS [55]. In addition, inflammatory monocytes recruited 24 h after L. major infection show NO-dependent leishmanicidal activity [56]. Furthermore, in vivo injection of these cells at the time of infection helped infected B6 mice to control skin lesions and reduce parasite burden [56]. Therefore, B6 inflammatory monocytes are effector cells against L. major parasites [55, 56].

Leishmania parasites that infect resident macrophages or inflammatory monocytes may have different fates, depending on the different stages of maturation and functional profiles of their host cells. In L. major infection, immature inflammatory macrophages fail to induce an M1 response in BALB/c mice. By contrast, in L. braziliensis infection, both B6 and BALB/c convert inflammatory macrophages to M1 (IL-12+ and iNOS+) phenotype and reduce arginase-1 expression [24]. Overall, these results agree with the idea that resistance to Leishmania infection correlates with inflammatory macrophage maturation into M1 in a mouse strain and Leishmania spp.-dependent fashion.

Nonetheless, monocytes may stand as a highly permissive niche for replication of Leishmania parasites in the dermis [51, 57, 58]. CD11b+Ly6C+ CCR2+ monocytes acquire an alternatively activated phenotype (CD206+arginase-1+) and provide a primary reservoir for parasite replication during the first few weeks of L. amazonensis infection, in spite of a strong Th1 response [51]. The dichotomy between the studies can be explained by the difficulty of identifying the resident or inflammatory macrophages, as well as the use of different mouse lineages, sites of infection, and Leishmania species (and strains), which can preferentially infect distinct host cells. Further investigation is required to address the functional phenotypes of resident and inflammatory macrophages and their consequences on parasite replication and the outcome of leishmaniasis.

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4. The interplay with neutrophils shapes macrophage phenotypes

The interactions between macrophages and neutrophils may regulate the course of Leishmania infection (Figure 1) [7]. There is a rapid recruitment of neutrophils to the site of infection with several Leishmania species in mice and hamsters [52, 59, 60, 61, 62]. Neutrophils can modulate the development of an anti-Leishmania immune response by secreting cytokines, chemokines, and granule contents, and by interacting with inflammatory monocytes, macrophages and DCs at the infection site [53, 63, 64, 65, 66]. The presence of neutrophils at the site of infection may contribute to the induction of a Th2-M2 response and correlate with susceptibility to L. major infection in BALB/c mice, where the percentage of neutrophils is maintained high and stable for weeks in the inoculated footpad. Accordingly, the depletion of neutrophils 6 h before challenge with L. major promotes partial resistance [63]. By contrast, neutrophils are only transiently recruited to the infection site in resistant B6 mice, while mononuclear phagocytes become the predominant cell population (80%) [52]. Nonetheless, by using the sandy fly model of L. major infection, the images obtained from the infection site revealed that many parasites are phagocytosed by neutrophils [62] and that dermal-resident macrophages became infected via phagocytosis of parasitized neutrophils [46]. These studies provide in vivo evidence for the “Trojan Horse” hypothesis in leishmaniasis, whereas the silent entry of the parasite into macrophages through the phagocytosis of infected and apoptotic neutrophils had been observed in vitro [67, 68].

Other studies that employed cocultured neutrophils and infected macrophages suggest that the interactions between these cells can have different consequences in L. major infection in a mouse strain-dependent manner [7, 65]. Neutrophil interaction with infected macrophages from B6 mice reduces parasite burden by activating macrophages to a leishmanicidal and tumor necrosis factor (TNF)-𝛼-producing phenotype via a TLR4 and neutrophil elastase (NE)-dependent pathway [64]. On the other hand, phagocytosis of apoptotic neutrophils by infected BALB/c macrophages promotes parasite growth [65]. Interestingly, B6 neutrophils release 2–3 times more NE than BALB/c neutrophils [64]. These results suggest that recruited B6 neutrophils shape macrophage phenotype to control parasite infection. However, if the clearance of B6 apoptotic neutrophils occurs prior to macrophage infection, it imprints an M2 regulatory phenotype (IL-12lowIL-10ℎigℎ), which is permissive to L. major replication and helps to establish infection [69]. It is conceivable that neutrophils might interact with macrophages both prior and after their infection with Leishmania parasites, leading to opposite outcomes.

Several receptors, including the Tyro-3, Axl, and Mer (TAM) receptors, contribute to the phagocytosis of apoptotic cells or efferocytosis. The TAM Axl and Mer receptors may play a role in the efferocytosis of infected apoptotic neutrophils and parasite transfer to macrophages and DCs in Leishmania infection [46, 70]. In addition, dermal-resident macrophages from Axl- and Mer-deficient mice showed reduced frequency of arginase-1+ cells and increased expression of iNOS. Therefore, the efferocytosis via TAM receptors polarizes dermal-resident macrophages to an M2 phenotype and contributes to early infection [46]. Axl−/−Mertk−/− mice also exhibited reduced parasite loads but had more severe pathology after sand fly-borne L. major infection [46].

The phenotypes of macrophages after interacting with neutrophils may also depend on the parasite species. Neutrophils and macrophages cooperate in L. braziliensis infection by promoting resistance in infected B6 and BALB/c mice [71]. In BALB/c experimental model, the depletion of neutrophils leads to a significant increase in the parasite load [72]. In addition, BALB/c mice inoculated with parasites and neutrophils exhibited lower parasite load at the site of infection and draining lymph nodes. In vitro, it was observed that neutrophils significantly reduced the parasite load in macrophages from BALB/c mice infected with L. braziliensis, an effect associated with an increase in TNF-α and superoxide production [72]. This outcome differs from the previous mentioned studies with L. major infection, where the interaction of infected BALB/c macrophages with apoptotic neutrophils favors the multiplication of the parasite [63, 65].

Neutrophils can also intervene in the macrophage phenotype by indirectly influencing the T cell response after interacting with DCs. DCs infected through efferocytosis of apoptotic and infected neutrophils fail to activate T cells in lymph nodes [53] and probably delay the Th1 responses that would activate M1 macrophages. There are other factors that can regulate macrophage phenotype during interaction with neutrophils. In natural Leishmania infection, sand fly saliva is inoculated in the dermal site of infection. The saliva components accelerate the apoptosis of inflammatory neutrophils [73] and upregulate the Th2 response while downregulating the Th1 response during L. major infection [74]. In addition, sand fly saliva components positively interfere with the production of prostaglandin E2 and IL-10 which can inhibit macrophage activation and reduce the production of TNF-α, NO, and H2O2, leading to a M2-parasite-permissive phenotype [75].

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5. The crosstalk with T cells modulates macrophage phenotypes

Many studies have characterized the participation of CD4 and CD8 T cells in both protection and pathology in Leishmania infection in mice and humans. M1 (classically activated) and M2 (alternatively activated) macrophages have been studied in the context of the Th1-Th2 paradigm [76]. The crosstalk between T cells and macrophages has been correlated with resistance versus susceptibility in models involving different Leishmania species and animal strains. While some studies demonstrate that Th1/M1 responses mediate immunity to L. major parasites in resistant B6 mice, Th2/M2 cells underlie susceptibility to L. major infection in BALB/c mice [10, 77]. The Th2 cytokines IL-4, IL10, and IL-13 produced during infection with L. amazonensis and L. panamensis can drive macrophage polarization toward the M2 phenotype, via activation of the enzyme arginase-1 and production of L-ornithine, favoring the survival and growth of Leishmania in macrophages, as well as disease progression [10, 32, 78]. In L. major-susceptible mice, arginase activity is directly related to parasite growth [79, 80] and the inhibition of its activity reduces parasite load [80, 81]. In vitro studies have already shown that L. amazonensis-infected BALB/c macrophages show increased L-arginine uptake and arginase expression [82].

The correlation between Th1-IFN-γ and macrophage-NO is reinforced in studies showing that mice deficient for the expression of IFN-γ or IFN-γ receptor in macrophages do not produce NO in response to various stimuli, suggesting that IFN-γ is a key inducer of iNOS [83, 84]. In addition, mice otherwise resistant to L. major infection that were deficient for the gene encoding iNOS [85] or treated with an iNOS enzyme inhibitor [86] became susceptible to infection. Similarly, other studies link the Th2-IL-4 and macrophage-arginase-1 axis to Leishmania susceptibility [87]. Although the role of IL-4 in Leishmania infection remains overall controversial [7, 20, 88, 89, 90], Holscher et al. have shown that interleukin-4 receptorα (IL-4Rα) deficiency in phagocytes results in a delay in the progression of leishmaniasis [87], probably by blocking alternative macrophage activation.

Finally, type 1 immune responses are not always beneficial to the host. An exacerbated Th1 cytokine response may contribute to the pathology in mucocutaneous leishmaniasis, for example during L. braziliensis infection [91, 92]. Interestingly, the IFN-γ produced by Th1 cells early during L. amazonensis infection mediates the expansion and recruitment of CCR2+ inflammatory monocytes that provide, at the site of infection, a reservoir of parasite-permissive cells that undergo alternative activation [51]. Therefore, the paradigm that establishes that resistance versus susceptibility correlates with macrophage activation is not absolute and needs further studies. Part of the problem relies on the need of complex subtyping of intermediate phenotypes lying between the extreme poles (M1 and M2) of macrophage activation [93].

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6. Tools for skewing M1 and M2 phenotypes and disease outcome

Leishmaniasis represents a major challenge for Public Health owing to the lack of vaccines, toxicity of available CL treatment, and their incomplete effectiveness [94]. Multiple factors can explain the difficult in generating new effective vaccines and lower toxic therapies, mainly the diversity of Leishmania species and the complexity of the host immune responses [95]. As an obligate intracellular parasite, residing inside macrophages, Leishmania evolved in contact with the host immune system, developing mechanisms to evade or modulate the immune response, which further hamper the development of vaccines [17, 33]. New avenues for the development of therapies aimed at the regulation, activation, or polarization/repolarization of macrophages bring hope for the treatment of leishmaniasis. Here, we discuss some studies (2011–2020) that show the potential use of therapies targeting M1/M2 plasticity in different Leishmania spp. infection and how each one can directly modulate macrophage phenotypes.

In PKDL caused by L. donovani, there is a decrease in the production of ROS and NO by monocytes and an increase in the expression of CD206 and arginase-1, which are hallmarks of M2 macrophages [33]. However, after chemotherapy with anti-leishmanial drugs, macrophages show an M1 profile, indicating that M2 to M1 repolarization can be considered as a therapeutic approach [33].

Macrophages infected with L. donovani acquire an M2 phenotype through the mammalian Target of Rapamycin (mTOR) pathway, as demonstrated in experiments where mTOR inhibition reduced M2 macrophages and parasite load. In vivo, the blockade of mTOR pathway increased NO, IL-12, and IFN-γ and reduced IL-10 and arginase-1 and parasite burden in the spleen [39]. Likewise, the treatment of L. amazonensis-infected macrophages with the snake venom component crotoxin increased the production of NO, IL-6, and TNF-α, which are hallmarks of M1 activation profile associated with leishmanicidal activity [96].

The alteration of miRNA expression in parasite infection has been studied in the context of macrophage plasticity. L. donovani, L. major, and L. amazonensis induce alterations of miRNA profiles in infected human and murine macrophages [32, 97, 98]. Inhibition of miR-294 or miR721/Nos2 interactions increased iNOS expression and NO production and reduced L. amazonensis infection. The role of miR-294 and miR-721 in the regulation of iNOS expression during Leishmania replication in infected macrophages points to miRNAs as targets for drug development [32]. Thus, microRNAs control macrophage plasticity, as mechanisms that sustain or impair the expression of M1/M2 genes, with the redirection of macrophage phenotype according to environmental signals [99].

In vitro activation of glucose-6-phosphate dehydrogenase (G6PDH) in L. major-infected macrophage regulates macrophage function, by increasing NO production and parasite killing [100]. The modulation of host metabolism during infection may represent a potential therapeutic target for treating leishmaniasis, and metabolic reprogramming of immune cells such as macrophages and monocytes could dictate their ability as effector cells or parasite-permissive reservoirs [101].

Recent studies showed that B6 peritoneal macrophages express the receptor RANK and the M2 markers CD301 (MGL) and CD206. The treatment of B6 macrophages with the T cell cytokines RANKL and IFN-γ induced M1 macrophages capable of producing IL-12, TNF-α, and NO but reduced MGL and arginase-1 expression. In addition, RANKL and IFN-γ increased NO production by BALB/c macrophages. Therefore, RANKL helps IFN-γ to induce a shift in macrophage phenotype from M2 to a M1 profile that is effective in controlling L. major infection [102].

By contrast, treatment of bone-marrow-derived macrophages with ATRA (all-trans retinoic acid) prevented the induction of M1 macrophages, promoting a shift from M1 to M2 phenotype [24]. After treatment with ATRA, inflammatory macrophages from B6 mice lost their ability to eliminate L. major parasites [24, 56]. In addition, mice treated with ATRA developed increased footpad lesions and parasite burden in draining lymph nodes [56]. After intraperitoneal injection, ATRA reduced pro-inflammatory cytokines, iNOS expression, NO production, and increased parasite infection in macrophages [24]. Possibly, ATRA downregulates inflammatory responses, by reducing the activation of nuclear factor-κB (NF-κB) in macrophages [103], whereas RANKL, in turn, induces the NF-κB signaling pathway and M1 responses [102]. Therefore, the NF-κB pathway might be at the crossroads of M1-M2 regulation and stands as a potential therapeutic target to potentiate immunity to infection or otherwise to reduce inflammation [103]. Whereas manipulation of macrophage phenotypes is a new perspective to direct the development of therapeutic strategies to intervene in multiple diseases, care is advised, considering the potential side effects on inflammation and host susceptibility to intracellular pathogens.

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7. Conclusion

The studies discussed here show that different manifestations caused by Leishmania infection rely on parasite-host cell interface. We also discussed how interactions with different species of Leishmania, innate cells, and adaptive immunity during infection generate changes in macrophage phenotypes and how this change of phenotype can alter the disease outcome in leishmaniasis. Leishmania species and different virulence factors may have an immunomodulatory effect on macrophages, leading to polarization toward an M2 phenotype, thus circumventing the host microbicidal mechanisms to favor their proliferation. On the other hand, M1 macrophages equilibrate between beneficial microbicidal activity and deleterious inflammatory response that can exacerbate lesions. The key to prevent pathogenesis in Leishmania infection may lie in a balance between resident and inflammatory macrophage phenotypes, particularly early in the infection, aiming to provide the best outcome to the host. Further studies will unveil the details involved in the complex balance between parasites and macrophages, providing new targets for future treatments and vaccines that shape macrophage phenotypes and control the pathogenesis of leishmaniasis. Finally, as immune responses against different types of leishmaniasis are multifactorial and distinct, we agree that the generation of different treatments or vaccines may be more effective than a single solution for leishmaniasis [17].

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Acknowledgments

The authors’ work cited here was supported by the Brazilian National Research Council (Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq, Brazil), the Rio de Janeiro State Science Foundation (Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, FAPERJ), the American Association of Immunologists (AAI), and the Oswaldo Cruz Foundation (Fundação Oswaldo Cruz, FIOCRUZ).

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Conflict of interest

The authors declare no conflict of interest.

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Written By

Natália S. Vellozo, Flávia L. Ribeiro-Gomes and Marcela F. Lopes

Submitted: 05 February 2022 Reviewed: 26 May 2022 Published: 16 September 2022