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

The response mediated by the M2c phenotype is basically induced by the stimulus provided by IL-10/transforming growth factor (TGF)-β, where post-differentiation transcriptome analysis indicates that this phenotype strongly regulates the expression of genes, such as CD163, MMP8, TIMP1, VCAM, SERPINA1, MARCO, PLOD2, PCOCLE2, and F5. Furthermore, the results of responses triggered by the production of these markers are directly associated with angiogenesis, remodeling of the extracellular matrix, and phagocytosis (Table 1) . 90 Regarding the M4 phenotype, the modulatory effect correlates strongly with the CXCL-4-mediated response that directly influences cell differentiation. 48, 91, 92 This was confirmed mainly by approaches investigating the development of atherosclerosis where the appearance of foamy macrophages with overexpressed genes, such as GM-CSF, CCL18, CD86, TNFSF10, ALOX5, IL1RN,and AIF1, induced production of pro-inflammatory mediators. In addition, development of the immune response in the processing and presentation of antigens by this cell triggers a regulatory phenomenon leading to overexpression of CD86, HLA-DRB1, HLA-DRB3, HLA-DRB4, and HLA-DQA1. 93 Interestingly, in the activation of an intracellular cascade that aims to regulate metabolism by accumulation of lipids, the cell overexpresses APOC2, APOE, and SORL1. 93 The purpose of the M4 phenotype study expanded to a set of interpretations, including the overexpression of chemotaxis-inducing genes (CCL3, CCL7, and CCR1) and cell adhesion where the cell overexpresses ITGAV, ITGA6, and ITGB8B. 93 The importance and relevance of the M4 phenotype in understanding atherogenesis indicate that M4 macrophages strongly express genes responsible for inducing proteases that degrade the extracellular matrix such as MMP7, MMP8, and MMP12. The results of the pathophysiological analysis of atherosclerosis investigated using transcriptome analysis shows that these cells express genes that facilitate the formation of foam cells such as CD36, MSR1, and ABCG1 by accumulation of LDL, which when metabolized, causes oxidative reactions that impair not only phagocytosis but also the destruction of microorganisms (Table 1) . 93, 94 Transduction signal and polarization of macrophage M1, M2, and M4 macrophages Investigation of the spectral role of macrophages began at the end of the 19th century, more precisely in 1883 with elaboration of the phagocytosis theory. 95 In 1905, Metchnikoff showed that phagocytic cells are able to destroy bacteriain infection persistent. 96 From that moment, the concept of macrophage activation began to be constructed. In 1964, the idea was further expounded, and between 1966 and 1971, lymphocytes were identified as the major antigen-specific cells responsible for macrophage microbicidal activation. [96] [97] [98] The discovery of IFN-γ in 1983 was the determinant for the proposal of the classical pathway of macrophage activation. 99 It is important to note that in 1986, the identification of the two subpopulations of T lymphocytes (Th1 and Th2) represented further advances underlying the emergence of the spectral macrophage concept. 100 In 1992, the concept of M2 macrophages began to be constructed, and in 2000, Mills et al 101, 102 proposed the classification of M1 and M2 macrophages based on the response mediated by Th1 and Th2 lymphocytes. Between 2002 and 2006, the concepts of activation, heterogeneity, and plasticity of M1 and M2 macrophages were amplified giv