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
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
2. Macrophage phenotypes in leishmaniasis
Although different species of
Recently, M1 and M2 macrophages were analyzed in skin biopsies from patients infected with several
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
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
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
At the beginning of
Nonetheless, monocytes may stand as a highly permissive niche for replication of
4. The interplay with neutrophils shapes macrophage phenotypes
The interactions between macrophages and neutrophils may regulate the course of
Other studies that employed cocultured neutrophils and infected macrophages suggest that the interactions between these cells can have different consequences in
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
The phenotypes of macrophages after interacting with neutrophils may also depend on the parasite species. Neutrophils and macrophages cooperate in
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
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
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
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
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
In PKDL caused by
Macrophages infected with
The alteration of miRNA expression in parasite infection has been studied in the context of macrophage plasticity.
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
By contrast, treatment of bone-marrow-derived macrophages with ATRA (all-
7. Conclusion
The studies discussed here show that different manifestations caused by
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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