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

In the case of bacteria, this relationship shows that contradictory events are associated with the response mechanism triggered by both enzymes. In leprosy, the in situ expression of iNOS is curiously predominant in the lepromatous form of the disease, whereas the immune response is directed more toward an immunosuppressive profile. Interestingly, in lepromatous leprosy, iNOS correlates positively with the expression of natural resistanceassociated macrophage protein 1 (NRAMP1), IL-22, and STAT3, indicating that the M1 phenotype is present in the tissue environment, generating reactive metabolites an attempt to eliminate the infection. Given that in this clinical form the anti-inflammatory response is more incisive, the development of the M2 phenotype fundamentally participates in inactivating the microbicidal response linked to Depending on the stimulus, cytokines, such as TNF-α and IFN-γ, may influence the process of shifting the M0 macrophage to M1. In this scenario, we highlight the performance of IFN-γ, GM-CSF, and TLR4 that influence development of intracellular cascade, which aims to produce of a series of markers to enhance the proinflammatory response in several aspects of classical pathway. In contrast, the antagonistic relationship between the duality of M1/M2 macrophages shows that IL-4 and IL-13 cytokines are mainly responsible for inducing differentiation of macrophages from M0 to M2. In the alternative pathway, activation of IL-4Rα or IL-10R shows that IL-4, IL-13, or IL-10 directly modulate development of anti-inflammatory responses and tissue repair. Through pathways of polarization, we emphasized the significance of M4 macrophages in the modulation of oxidative stress response as well as tissue repair. This relationship is particularly important in pathophysiology of atherosclerosis, where formation of foam cells due to LDL accumulation and low phagocytosis implies a regulatory phenomenon that triggers the production of TNF-α, IL-6, MRP8, MMP7, and MMP12. the M1 phenotype. It is precisely because of this that the tissue damage is much more obvious, and the associated response includes the exacerbated expression of Arg1, IL-4, IL-10, TGF-β, and FGFβ. [152] [153] [154] With regard to Mycobacterium tuberculosis, the response mediated by iNOS is more complex. Several seminal studies have shown that, as in leprosy, in tuberculosis iNOS exerts microbicidal activity. 155, 156 However, one of the final products generated in the metabolic cascade of iNOS favors the development of an intracellular signaling mechanism that controls inflammation. In this context, NO is able to inhibit the expression of NF-κB, one of the major transcription factors responsible for inducing the production of pro-inflammatory cytokines such as IFNγ and TNF-α. 157 Controversial events in the immunopathogenesis of M. tuberculosis infection are crucial in the interpretation of iNOS and Arg1 responses when the tissue microenvironment in tuberculoid granulomas are analyzed. The duality of the polarization of the relationship between M1 and M2 macrophages in both human and monkey granulomas, the anti-inflammatory phenotype (CD163 +iNOS+Arg1 high ) is located in more external areas, whereas in the internal portion, the pro-inflammatory phenotype (CD11C+CD68+CD163 dim iNOS+eNOS+Arg1 low ) is predominant. Therefore, in the same tissue environment, the presence of the M1 and M2 phenotype is crucial to maintaining the balance of the immune response and tissue d