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

ation mainly by IFN-γ, LPS, and TNF-α. 82 However, an interesting approach has shown that the M1 phenotype is dependent on transient receptor potential cation channel subfamily C member 3 (TRPC3) to activate calcium/calmodulin-dependent protein kinase II alpha (CAMK2) and STAT1, and activation of intracellular signaling mechanisms that influence the production of apoptotic markers. 83 As for the M2 phenotype, regulation of the alternative pathway results in interaction of different stimuli that modulate gene expression in different cellular environments. For example, in mice, the M (IL-4) regulates expression of pStat6, pStat1, ifr4, Socs2, ccl17, Ccl22, Ccl24, and Arg1. In humans, modulation of IRF4, SOCS1, GATA3, CCL13, CCL17, CCL17, CCL18, MRC1, STAB1, MARCO, CD163, FN, TGFB1, MMP1, MMP12, TG, F13A1, TGM2, ADORA3, TGFBR2, IL17RB, ALOX15, and CD200R occurs (Table 1) . 80, 84 Expression of Arg1 is classical evidence of the presence of the repair phenotype. In addition, cytokines such as IL-4 and IL-13 are required to establish cell differentiation. The transcriptome can aggregate a standard of analysis for the M2 phenotype characterized mainly by the expression of M130, CD163, CD206, MRC1, CCR7, МСР-3, FceRII, CD23, GPR86, GPR105, TLR-2, P2Y8, P2Y11, P2Y12, dectin-1, DC-SIGN, CD209, DCIR (CLECSF6), CLACSF13, FIZZ1, ST2 (SR-A, М60), CD184, TRAIL, STAT6, IL-27Ra, Chil3, Retnla, Ppar-γ, ARG1, TGF-β, IL-4, IL-5, IL-10, and IL-13 (Table 1) . 85, 86 It is noteworthy that transcriptome analysis has enabled elucidation of mechanisms underlying the modulation of IL-4 intracellular signaling by the induction of zinc finger TFs, Egr2, and c-Myc expression. As a final outcome, ingenuity pathway analysis shows that expression of these markers is directly involved in cell cycle progression in tumorigenesis. 34 How the M2 phenotype converts to M2a, M2b, or M2c depends highly on the stimuli provided. 87, 88 The M2a phenotype is generally observed after exposure to IL-4/ IL-13, which induces this phenotype during the process of immunoregulation, tissue repair, and tumor progression. 34 Transcriptome analysis reveals modulation of M2a, which shows that the response triggered by this cell is quite ambiguous and mainly involves polarization of the response between M1 and M2 macrophages. This is because the M2a phenotype can activate genes that regulate pro-and anti-inflammatory responses. Confirmation of such a situation is centered on the exacerbated expression of cytochrome c oxidase subunit 5A (COX5a) and WNT5b. 89 In contrast, previous reports have documented that the M2a phenotype cannot process an adequate response to produce pro-inflammatory cytokines and mediate an efficient microbicidal effect.