Functional aspects, phenotypic heterogeneity, and tissue immune response of macrophages in infectious diseases

de Sousa, Jorge Rodrigues; Da Costa Vasconcelos, Pedro Fernando; Quaresma, Juarez Antonio Simões

αR), whose main event is the development of intracellular cascade based on the activation of JAK1 and JAK2 and STAT1 or STAT2 responsible for inducing the production of MHCII, IL-12, and iNOS. [126] [127] [128] We cannot fail to mention the importance of GM-CSF in mediating NOS2 production. MHC class II, IL-12b, which is dependent on the activation of JAK2 and STAT5 and phosphorylation of IRF5. 129, 130 In addition to a set of immunological strategies mediated by response of M1 macrophages, TLR4 recognizes LPS, one of the major components produced by gram-negative bacteria, which activates NF-κB, AP1, and the production of TNF-α, IL-1β, IL-6, and IFN-γ ( Figure 2 ). [131] [132] [133] As an alternative pathway, M2 macrophages respond to stimulation by IL-4, IL-10, or IL-13 to mediate the development of the repair phenotype. By binding to their respective receptors, these cytokines can trigger activation of repair signaling cascades that modulate the activation and phosphorylation of JAK1-3, STAT3, STAT6, peroxisome proliferator-activated receptor γ (PPARγ) or phosphoinositide 3-K (PI3K) in order to induce production of Arg1, CD206, chitinase-like 3 (Chi313), reticulon-like A (Rtnla), TGF-β, NOS2, IL-4Rα, and IL-1Rα ( Figure 2 ). 134, 135 M4 macrophages have attracted attention in the research community due to their relationship to M0 macrophages. Specifically, their exposure to CXCL4 was shown to lead to the production of CD68, IL-6, TNF-α, S100A8, MMP7, and MMP12. 136, 137 M4 macrophages are highly enriched in atherosclerotic lesions, where the cells exhibit increased expression of LDL receptors. [138] [139] [140] This phenomenon causes accumulation of fat inside phagocytes, leading to the development of atheroma plaques and, consequently, oxidative lesions. [138] [139] [140] Although more comprehensive studies must be conducted to further elucidate the roles of M4 macrophages in the pathogenesis of diseases, the functions are probably related to an immunosuppressive environment targeting infectious pathogens ( Figure 2 ). [141] [142] [143] Antagonistic phenomena and duality of response between inos and arg1 and its relationship with M1 and M2 phenotype in infectious diseases Macrophages are one of the primary cell types that exert microbicidal activity against several groups microorganisms via polarization and duality of the response between the M1 and M2 phenotypes. [144] [145] [146] Therefore, an intriguing relationship is established in infectious diseases due to what happens intracellularly. [144] [145] [146] Classically, iNOS and Arg1 are characteristic and determinant markers for modulating the response of either M1 (iNOS) or M2 (Arg1) macrophages. [147] [148] [149] The resulting effects of these enzymes demonstrate that both compete for the same substrate (arginine) in order to induce the production of NO (M1) or proliamines and proline (M2). This antagonistic relation causes a phenomenon of duality that facilitates the destruction or survival of microorganisms. [149] [150] [151] In light of this phenomenon, we highlight the evolution of the understanding of this ambiguous relationship mainly in leprosy, tuberculosis, and leishmaniasis.