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

Macrophages can acquire microbicidal properties after stimulation by microbial products, acting in both innate and adaptive immunity mechanisms. One of the main strategies used by microorganisms to escape this macrophage activity involves altering the response profile of macrophages. 185, [235] [236] [237] [238] [239] [240] [241] [242] [243] [244] [245] [246] [247] [248] [249] [250] [251] [252] The activation of a response profile mediated by M1 macrophages is commonly associated with a protective tissue environment and has been described for infections by pathogens such as Helicobacter pylori, M. tuberculosis, Mycobacterium leprae, Salmonella typhi, and Chlamydia. 253-258 M1 macrophages elicit an effective immune response against S. typhi and H. pylori, and in the response against H. pylori, the induction of iNOS associated with the M1 profile is closely related to the occurrence of gastric cancer. [259] [260] [261] [262] [263] [264] Early and acute stages of M. tuberculosis infections are mediated by M1 macrophages. In the later stages and chronic disease, the infection is associated with responses mediated by M2 macrophages, whose weak microbicidal activity and ability to eliminate bacteria are linked to the occurrence of the lesions observed during disease evolution. [265] [266] [267] [268] [269] In leprosy, macrophages are the primary cells that exert microbicidal activity. Thus, the role of macrophages in the response to M. leprae has been widely described and is correlated with the expression of certain cytokines that are classical representatives of the cellular immune response, such as TNF-α and IFN-γ. [270] [271] [272] In leprosy, when TNF-α and IFN-γ bind to their specific receptors, the behavior of M0 macrophages is altered. Furthermore, after undergoing phenotypic modification, the M0 macrophages become inflammatory, producing inflammatory cytokines and enzymes such as iNOS, which produces NO and, consequently, reactive oxygen radicals, leading to the destruction of the bacteria. [273] [274] [275] In contrast, M2 and M4 macrophages are observed mainly in lepromatous lesions, and both cell types present expression profiles associated with immunosuppressive cytokines. Therefore, these cells are likely to be related to more diffuse and severe aspects of the disease. These features are also observed in tegumentary leishmaniasis, where M2 macrophages are related mainly to diffuse and anergic aspects of the disease. [276] [277] [278] In viral diseases, the macrophage response might be subverted to a certain extent by the numerous escape mechanisms that viral agents use to resist the host immune response. [279] [280] [281] [282] [283] [284] [285] [286] [287] [288] [289] Nevertheless, viruses generally trigger a response mediated by M1 macrophages that might contribute to the severity of the disease. In hepatitis C, chronic infection can lead to cell damage and cirrhosis, and the virus can induce an immune response, targeting the viral protein NS3, mediated by IL-12 and TNF-α produced by M1 macrophages. This process creates a pro-inflammatory environment that contributes to the induction of cell injury. A similar process occurs in the liver of patients infected with dengue virus and yellow fever, where cytokines, such as TNF-α and TGF-β released by Kupffer cells, contribute to the development of a pro-inflammatory and proapoptotic environment in tissue hepatic necrosis, which leads to massive apoptosis of hepatocytes because of the