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

The recently discovered M3 macrophages are known as commuting macrophages. The first study discussing the emergence of this previously unknown lineage showed that their appearance depended on the switching response between M1 and M2 macrophage pathways (Table 1) . 63 M4 macrophages, similar to M3 macrophages, represent a group of newly identified cells that have attracted much attention in research because of the response mechanisms they can develop. 48, 64 M4 macrophages differentiate in the presence of colony-stimulating factor (CSF) and (CXCL4). The markers of these cells are CD206, CD68, metalloproteinase 7 (MMP7), MMP12, and calcium-binding protein A8 (S100A8); the cells produce IL-6, TNF-α, and CCL18 and CCL20. 65,66 M4 macrophages highly express the low-density lipoprotein (LDL) receptor, and in chronic lesions, these cells form a large contingent of foam cells that in the inflammatory process (Table 1) . [67] [68] [69] Lastly, the concept of cell emergence in the case of M17 macrophages is new. One of the earliest studies supporting this hypothesis showed that cell formation can be induced by corticosteroids, granulocyte-macrophage (GM)-CSF, or IL-10, and a key feature is the cells that respond to IL-17 become resistant to apoptosis (Table 1) . 70 Markers of M1, M2, and M4 macrophages With advances in technology, discovery of the transcriptome has allowed for identification of several genes related to the phenotypic modulation of macrophages. 71, 72 This transcriptomic characterization of the phenotypes M1, M2, and M4 is a topic that needs to be addressed. 73, 74 For instance, the integrated network established by a combination of factors typically characterizes a complex phenomenon where real-time polymerase chain reaction (PCR) validation, for example, shows that the expression of CD38, Gpr18, and Fpr2 is exclusive to the M1 phenotype. 75 The importance of this relationship is the fact that these newly identified markers are essential to cell activation and the oxidative stress mechanism. 76 Without disregarding findings previously confirmed by other techniques, the transcriptome study reaffirmed the expression of classical markers that affect not only cell activation but also differentiation and development of the pro-inflammatory response. Therefore, IFN-γ, TNF-α, LPS, IFN-β, iNOS, IL-1β, IL-6, IL-12, B7, B7.1, MCP3, IP-10 or CXCL10, CD16, CD32, CD62, CTLA8, and α-chain still represent a set of fundamental markers that characterize activation of the classical pathway (M1). [77] [78] [79] In situations where the stimulus is mediated by LPS + IFN-γ, there is an increase in expression of pSTAT1, pSTAT6, Socs1, NF-kB Nfkbiz, IRF5, IRF1, TNF, II6, II27, IL23a, II12a, CCL5, CXCL9, CXCL10, CXCL11, NOS2 , GBPI, CCR7, and CD40 on M1 macrophages (Table 1) . 80 In humans, a very peculiar phenomenon occurs by polarization of the response between M1 and M2 macrophages, attributable to the M1 phenotype expression of Wnt family member 5A (WNTA5A) and glycerol-3-phosphate dehydrogenase 2 (GPD2) and modulation of oncogenesis and mitochondrial stress. In addition, another important discovery made using transcriptome analysis and in vitro experimental models is that CD120b, Tolllike receptor 2 (TLR2), SLAM family member 7 (SLAMF7), and chemotactic factors, such as CXCL8, CCL5, CCL2, and IL-6, regulate the M1 phenotype matrix. 81 Considerable data support that polarization via the M1 phenotype classically conjugates the result, such as stimul