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

val strategy, L. donovani also prevents apoptosis triggered by oxidative stress, inducing SOCS1 and SOCS3 production. 180 Interestingly, that in Leishmania amazonensis, the intracellular regulatory effect anchored in the action of protein kinase triggers production of IFN-β, which in turn, increases expression of superoxide dismutase 1 (SOD1), inhibiting destruction of the parasite and facilitating its proliferation (Figure 3 ). 181 Regarding Trypanosomiasis cruzi, TLRs play a crucial role in resistance to the protozoan infection in macrophages, where GPIs and mucins modulate the behavioral difference among TLR2, TLR4, TLR7, and TLR9. In fact, this relationship mainly affects the production of Th1 cytokines. Notably, in TLR2-deficient mice, a potent proinflammatory response was observed, mainly induced by IFN-γ. 181, 182 One of the central questions surrounding the strategies of immune evasion by M. tuberculosis, Leishmania, or T. cruzi is the mechanism underlying phagosome maturation modulation. [183] [184] [185] This has direct implications on the biogenesis of the phagolysosome. To survive in a hostile environment, these microorganisms have developed a series of mechanisms aimed at neutralizing one of the cell's primary lines of defense. It starts at the point of inhibition of the inflammatory cytokine response (IFN-γ or TNF-α), where this relationship influences the endosome immaturity. [186] [187] [188] Incidentally, Rab family proteins are actively involved in this process. In this context, Rab5 and 7 are directly related to the early and late fusion of the endosome and lysosome, respectively. The stage of immaturity of the phagosome is organized in this duality of interaction between early and late fusion. [189] [190] [191] Therefore, microorganisms initially maintain Rab5 expression in order to facilitate recruitment of coronin 1a protein and the development of the calcium-calcineurin signaling pathway whose final outcome is the loss of fusion of the phagosome with the lysosome (Figure 3 ). [192] [193] [194] The implications of this catastrophic cellular effect include the inhibition of late markers such as Rab7 and the loss of various hydrolases such as cathepsin D. Another final point that dramatically impacts the immune escape of pathogens is inhibition of PI3K, which deregulates the gallbladder traffic in the Golgi apparatus ( Figure 3 ). [195] [196] [197] Virus Currently, the action of macrophages has not been shown to be directly related to the antiviral response. This is attributed to the fact that TLR3, TLR7, TLR8, RIG-I, and MDA5 are largely produced by the cell. In this context, the modulation of viral replication starts from information that is passed to the cytoplasm where RIG-1 and MDA5 recognize single-stranded RNA viruses to facilitate the formation of the IKK complex (α, β, and γ). Consequently, the phosphorylation and migration of NF-κB and IRF3 and 7 to the nucleus activate genes responsible for inducing the production of IFN-α and β ( Figure 4 ). [198] [199] [200] However, the strategies used by the virus modulate the immune evasion mechanism, whereas non-structural NSs of DENV, WNV, ZIKV, and HCV flaviviruses inhibit activation of RIG-I and MDA5 as well as a series of intracellular markers during the inactivation of molecules such as STING, MAVS, and NF-κB. This mechanism directly affects the inhibition of ISGs, Mx, OS, PKR, and the production of IFN-α and β. In the case of type 1 IFN, intracellular signalin