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 have failed to develop an effective response against certain intracellular pathogens. 162, 163 The reason for this failure has been a long-standing question in this field. Thus, numerous studies have sought to elucidate the pathway through which the behavior of an infected cell is altered. Regardless of whether a cell is infected by viruses, bacteria, protozoa, or fungi, the pathogen in each case uses the immune system to modulate the response and, thereby, survive inside the cell. [163] [164] [165] Bacteria and protozoa One of the key issues arising from the discussion of this subject is understanding the response that PRRs can induce through the recognition of PAMPs of certain microorganisms. Classically, receptors such as those in the Toll family agglutinate a variable range from TLR1 to TLR13. [166] [167] [168] Therefore, in the case of mycobacteria, the importance of TLR2, TLR4, and TLR9 in the development of the microbicidal response is paramount since the regulation of the intracellular cascade involves the binding of MyD88 and Mal, also known as TIRAP, which recruits IRAK1/4, TRAF6, and TRICA1 to induce the production of mitogen-activated protein kinase (MAPK) and NF-κB. [169] [170] [171] As a final outcome, NF-kB is responsible for inducing the production of pro-inflammatory cytokines such as TNF-α, IFN-γ, IL-1β, and IL-6 that participate in the activation of macrophages and enzymes such as iNOS, which is responsible the generation of ROS and destruction of the microorganism. 126, 172, 173 However, the immune evasion strategies adopted by mycobacteria include a series of events aimed at inactivating this mechanism. With regard to M. tuberculosis, TLR2 is the main receptor by which mycobacteria modulate immune escape. Therefore, the interaction between TLR2, ESAT-6, and CFP-10 drastically suppresses the immune response of macrophages by inhibiting NF-κB activation, iNOS, and NO production. 174 Nevertheless, recognition events of PAMPs show that M. tuberculosis mutants produce sulfoglycolipids that antagonize the activation of both TLR2 and NF-κB. 175 Interestingly, in this same dynamic, the bacterium can subvert the TLR2-MyD88 pathway and facilitate its translocation into the cytosol. The consequences of this modulation include the direct involvement of H37Rv strains and the escape of the phagosome or phagolysosome. 176 It is worth mentioning that immune evasion via modulation of TLR2 by the recombinant lipoprotein Rv1016c, induces apoptosis of macrophages by increasing annexin expression. 177 Consequently, this relationship becomes beneficial because in addition to Rv1016c inhibition of MHC-II expression, TLR2-dependent apoptosis may promote the release of residual bacilli into apoptotic cells and, thereby, decrease the recognition of CD4+ T cells, impairing surveillance in chronic disease conditions (Figure 3 ). 177 Concerning protozoa, one of the main parasites that compromise macrophage activity is Leishmania. 163 L. major negatively modulates TLR2 receptor activity to increase the recruitment of SOCS1 and SOCS3, which inhibit the production of NF-kB, IFN-γ, and TNF-α in order to establish pathogen survival. 178 In Leishmania donovani, the amastigote forms and TLR2 suppress the inhibitor of NF-kB kinase (IKK)-NF-kB complex and the positive regulation of the enzyme deubiquitinating A20. 15, 179 As a result, this process facilitates the degradation of TRAF6 and inhibition of the TNF-α and IL-12 response. As a survi