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

en the diversity of a set of experimental models, which heralded the appearance of M2 subtypes M2a, M2b, and others. [103] [104] [105] [106] However, the theoretical basis of the response behavior of macrophages indicates a complex relationship, mainly with polarization. In 2010, Biswas and Mantovani 107,108 showed a response paradigm between M1 and M2 macrophages. Finally, during the last few years, technological advances have led to deeper discussions on the polarization of response of M1 and M2 macrophages. In 2014, Murray et al 80 attempted to standardize terminology regarding macrophage polarization concepts from the responses obtained in several experimental models. However, problems still exist at the conceptual level, particularly regarding the stabilization of macrophage subpopulations through their participation in pathophysiological, pathological, and immunological mechanisms ( Figure 1 ). [109] [110] [111] Following the identification of the M2 phenotype, studies began to emerge demonstrating that two distinct types of macrophages were present, which were each associated with a distinct activation pathway. In the classical pathway, the main cells are M1 macrophages, also known as inflammatory macrophages and microbicides. In the alternative pathway, also known as the reparative pathway, cells responsible for the repair response are the M2 macrophages. [112] [113] [114] Considering the versatility of macrophages, their response mechanisms in destroying microorganisms appear to include aspects of the immune response that remain incompletely elucidated. However, current evidence further strengthens their relationship with components of the innate and adaptive immune systems. 115, 116 In the innate immune response, when macrophages exposed to certain stimuli, such as LPS-peptide complexes, are recognized by TLRs and CD14, signaling cascades might be initiated that generate reactive oxygen and nitrogen species and inflammatory cytokines such as IFNα and IFN-β. [117] [118] [119] During the humoral response, phagocytosis of certain microorganisms might be mediated by recognition of the Fc portion. 120 Specific costimulatory molecules act as a key step in enhancing phagocytosis, antigen presentation, and endocytosis. These molecules belong to the family of receptors known as scavenger and mannose receptors. 121 During the innate response, certain components of the complement system regulate polarization of the macrophage response. In the inflammatory pathway, some complements, such as C3a, C5a, C5b, and C9, might induce production of inflammatory mediators. In the regenerative pathway, the presence of opsonized apoptotic bodies with fragments of complement C1q or C3b might stimulate M2 macrophages to produce Arg and anti-inflammatory cytokines. 122 The classical signal-transduction response scheme described for both M1 and M2 macrophages follows a pathway starting from the binding of a protein or some other component to a receptor, which initiates a signaling cascade involving signal transduction through phosphorylation of transcription factors, migration of the factors to the nucleus, activation of genes, and production of molecules such as cytokines, enzymes, and costimulatory molecules. 21, [123] [124] [125] In the classical pathway, we highlight three routes that are essential to the modulation of the microbicidal activity of M1 macrophages. The first is the binding of IFN-γ or TNF-α to their respective receptors (IFN-γR or TNF-