Leishmaniasis: Immune Cells Crosstalk in Macrophage Polarization

Abstract

Leishmaniasis is a complex infectious parasitic disease caused by protozoa of the genus Leishmania, belonging to a group of neglected tropical diseases. It establishes significant global health challenges, particularly in socio-economically disadvantaged regions. Macrophages, as innate immune cells, play a crucial role in initiating the inflammatory response against the pathogens responsible for this disease. Macrophage polarization, the process of differentiating macrophages into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, is essential for the immune response in leishmaniasis. The M1 phenotype is associated with resistance to Leishmania infection, while the M2 phenotype is predominant in susceptible environments. Notably, various immune cells, including T cells, play a significant role in modulating macrophage polarization by releasing cytokines that influence macrophage maturation and function. Furthermore, other immune cells can also impact macrophage polarization in a T-cell-independent manner. Therefore, this review comprehensively examines macrophage polarization's role in leishmaniasis and other immune cells' potential involvement in this intricate process.

Keywords: immune response; leishmaniasis; macrophage phenotype.

Figure 1

Classically and alternatively activated macrophages. Macrophages represent an essential innate immune cell component characterized by their plasticity. When exposed to specific microenvironmental conditions, macrophages can suffer polarization, originating distinct phenotypes. For instance, cytokines such as IFN-γ and TNF-α (also expressed by Th1 cells) can lead to the polarization of M0 macrophages into pro-inflammatory profiles called classically activated macrophages (M1). These subpopulations are characterized by the expression of surface markers (TLR-2, TLR-4, CD80, CD86, MHC-II) and secretion of cytokines and chemokines such as TNF-α, IL-1β, IL-6, CXCL9, and CXCL10. On the other hand, alternatively activated macrophages (M2) can be generated through interaction with Th2 cytokine profiles like IL-4, IL-13, and IL-10 and can express CD206, CD163, and CD209. Noteworthy, based on the stimulus that these cells are exposed to, M2 macrophages can be divided into four subtypes with distinct phenotypes: M2a (generated by interaction with IL-4 and IL-13), M2b (activated in response to lipopolysaccharide (LPS), IL-1β, TLR agonists and some immune complexes), M2c (via IL-10, TGF-β, and glucocorticoids) and M2d (activated by IL-6, TLR, and A2A adenosine receptor agonists). Created with BioRender.com.

Figure 2

Immune modulation of macrophages during leishmaniasis. (A). Visceral Leishmaniasis has higher serum levels of pro-inflammatory cytokines IFN-γ and IL-12 and immunosuppressors IL-10. IL-12 can be expressed by infected dendritic cells, and such as INF-γ can drive to Th1 response. On the other hand, cytokines characteristics of the Th2 subtype, like IL-4, IL-5, and IL-13, lead to the growth of the parasite and help in the persistence of infection in chronic diseases. They also negatively modulate the oxidative burst in macrophages. Moreover, CD206 and CD163, markers that favor M2 polarization, had increased expression in macrophages infected with Leishmania donovani. (B). TNF-α is an essential cytokine in promoting M1 polarization. In animal models, the deficiency of these proinflammatory molecules during Leishmania major infection leads to a severe disease progression with a decrease in M1 macrophages and enhancement in M2 phenotype formation, suggesting the rule of these inflammatory profiles in control of infection. Moreover, Leishmania amazonensis can modulate NRLP3 inflammasome complexes and reduce positive NF-kB regulators like IL18R1, TNFRSF1A, Toll-like receptor 4 (TLR4) and MYD88 and increase anti-inflammatory molecules as TOLLIP, an inhibitor of TLR. Created with BioRender “https://app.biorender.com/ (accessed 21 April 2023)”.

Figure 3

Crosstalk between immune cells in macrophage polarization. Macrophage polarization could be modulated by different cells in a microenvironment-dependent manner. (A) Regulatory T cells (Treg) can induce M2 phenotype by releasing cytokines (e.g., IL-10, IL-13, and TGF-β). (B) B cells can induce macrophage towards also to an M2 phenotype by releasing IL-10 and supporting Th2 polarization, a known cell to induce M2. (C) Innate lymphoid cells (ILCs) can promote M1 and M2 polarization, mostly by releasing cytokines. ILC2 releases M2 phenotype inductor cytokines (e.g., IL-4), while ILC1 and ILC3 induce M1 phenotype by secreting IFN-γ and IL-17A, respectively. M1 macrophage can activate NK cells, which can lysis M2 macrophages, but not M1 macrophages. (D) NKT1 cells can support Th1 polarization and, thus, M1 phenotype while can reduce M2 CD206+ frequency. M2 polarization can be inhibited by NKT2 cells. (E) In specific microenvironmental conditions, M2 macrophages can attract neutrophils by releasing CXCL-1. In turn, neutrophils have a dual role in macrophage phenotype. Through TNF-α and neutrophil extracellular traps release, M1 polarization prevails. In contrast, releasing other cytokines (i.e., CSF-1, IL-13, and TGF-β) and efferocytosis (i.e., macrophage phagocytosis of apoptotic neutrophils) lead to M2 polarization. Created with BioRender “https://app.biorender.com/ (accessed 21 April 2023)”.