Fig. 3

TRMs in inflammation and homeostasis. a The canonical pro-inflammatory response is initiated by either PRRs or opsonin receptors. PRRs can directly recognize DAMPs (usually cell-derived molecules, e.g., Biglycan, versican, F-actin) and PAMPs (usually microorganism-derived molecules, e.g., Foreign DNA, flagellin, mannose). The opsonin receptor-mediated recognition process involves binding foreign particles labeled by opsonins and opsonic receptors, including Fcγ receptors. The recognition activates actin polymerization, pro-inflammatory cytokines, and other responses. The phagosome fuses with the lysosome. In late endosomal MIICs, most newly synthesized MHC-II molecules are likely loaded in an HLA-DM-dependent mechanism. The antigens and MHC-II will form MHC-II peptide complexes and then be delivered to the plasma membrane to be available to stimulate antigen-specific CD4⁺ T lymphocytes. Pro-inflammatory cytokines (e.g., TNF-α, IL-1β, LPS). b Resolution of inflammation. Apoptotic cells can release “find me” signals (EG. ATP, Lys phosphatidylcholine, CX3CL1) to recruit TAMs. Phagocytosis is facilitated by receptors (e.g., BAI1, Mer, Axl, αvβ3-integrin) directly binding with eat-me signals (e.g., PtdSer, Calreticulin, LPC) on apoptotic cells or indirectly recognizing bridging molecules, such as MFGE8, C1q, protein S, etc., which bind to eat-me signals. The recognition activates actin polymerization, immune-resolution cytokines, and other responses. Pro-inflammation cytokines (TNF-α, IL-6, etc.) decrease, and immune-resolution cytokines (IL-10, TGF-β) increase. Some viruses display PtdSer on their surface and mimic apoptotic cells, which allows them to evade the immune system and facilitate entry into host cells. Tolerant responses have also been attributed to Dectin-1/2 and SIRPα. Altered glycosylation is a universal feature of cancer cells; some abnormal glycans (e.g., galectin 9) promote cancer growth and immune tolerance through Dectin 1/2 activation. Some tumor cells express CD47 that interacts with SIRPα, expressed on the surface of macrophages and dendritic cells, inhibiting phagocytosis and maintaining self-tolerance. c TRMs sense physical factors and cytokines in the microenvironment. SIRPα signal regulatory protein alpha, LPC lysophosphatidylcholine, PRRs pattern recognition receptors, PAMPs pathogen-associated molecular patterns, DAMPs damage-associated molecular patterns, MIIC MHC class II compartment, LPS lipopolysaccharides, LPC lysophosphatidylcholines, HLA human leukocyte antigen