Fig. 2

Receptors sense endogenous DAMPs activation intracellular signals. Receptors sense endogenous DAMPs activation intracellular signals. TLRs: TLRs can sense a variety of DAMPs. TLR2 and TLR4 recognize various DAMPs such as HMGB1, HSP, S100 protein, Histone, Hyaluronan, and Biglycan. Activated TLR2 and TLR4 recruit MAPK and IKK signals through cytoplasmic adapter MyD88. Results in activation of transcription factors NF-κB and activator protein 1 (AP-1), which mediate cytokine transcription. In addition to the MyD88 pathway, TLR4 also activates MAPK and IKK through TRIF. TLR3 and TLR9 are activated by endosomal nucleic acid. Like TLR2 and TLR4, TLR9 activated downstream signals through the MyD88 pathway, while TLR3 induced downstream signal activation through the TRIF pathway. CLRs: CLRs, a type of PRRs, contains multiple members, such as Clec2d, Mincle, and DNGR-1. Clec2d can be detected in cell membrane and endosomes. DNA-binding histones stimulate and activate endosomal TLR9 in a Clec2d-dependent manner, and induces inflammatory response. Mincle, another CLRs member, recognizes Sin3A-associated protein 130 (SAP130) and activates downstream MAPK signal through phosphorylation of spleen tyrosine kinase (SYK). SYK phosphorylation can also activate NF-κB through the assembly of caspase recruitment domain-containing protein 9 (CARD9) complex and promote the production of inflammatory factors. Unlike Clec2d and Mincle, DNGR-1 recognizes dead cell debris and promotes cross-presentation of associated antigens. DNGR-1 binds to the ligand filamentous actin(F-actin) to activate SYK. Phosphorylated SYK activated NADPH oxidase (NOX), causing the phagosome damage, and the phagosome contents to escape into the cytoplasm and access the endogenous major histocompatibility complex I antigen processing pathway, enabling MHC class I antigen to present exogenous antigens, thereby promoting the cross presentation of dendritic cells.²⁸³ RAGE: RAGE interacts with HMGB1 and S100s. Stimulated RAGE activates NF-κB and AP-1 through PI3K/AKT and MAPK pathways, promoting inflammatory response. P2X7: P2X7 receptors are activated by ATP to form non-selective ion channels that promote K⁺ efflux and Ca²⁺ influx. K⁺ efflux is critical for activation of NLRP3 inflammasome, which cuts pro-caspase-1 to form active caspase-1 and promotes IL-1β and IL-18 production. In addition, there is evidence that Ca²⁺ influx is involved in NLRP3 inflammasome activation