Fig. 3

Key signaling pathways in atherosclerosis. a TLR signaling pathway. TLR stimulation triggers MyD88 to interact with IRAK4 (interleukin-1 receptor-associated kinase 4), which transmits signals into NF-κB and MAPK to activate the expression of inflammatory cytokines via the MyD88-dependent pathway. Endosomal TLRs transmit signals through the TRIF-dependent pathway. TRIF together with RIP1, TRAF6, and Pellino-1 activate TAK1 or with noncanonical TBK1 (Tank-binding-kinase 1) and IKKε (IKKi) activates interferon regulatory factor 3 (IRF3) and 7 to induce inflammatory cytokines. b NLRP3 inflammasome pathways. The activation of NLRP3 inflammasome has two steps: the priming and the activation. The priming is triggered by endogenous cytokines or microbial molecules. The activation of NLRP3 inflammasome includes canonical and noncanonical pathways. The canonical activation induces caspase-1 activation, which processes pro-IL-1β/pro-IL-18 to IL-1β/IL-18 active form. The noncanonical activation induced by mouse caspase-11, and human caspase-4 and caspase-5, indirectly promotes the expression of pro-IL-1β/pro-IL-18. Activated caspase-1 and caspase-11 can cleave GSDMD (gasdermin D), leading to the formation of pores in the plasma membrane and causing pyroptosis and the release of IL-1β/IL-18. c PCSK9 pathways. The expression of PCSK9 can be activated by oxLDL, LPS, and pro-inflammatory cytokines in ECs, VSMCs, and macrophages. In the absence of PCSK9, the LDL–LDLR complex is internalized. Subsequently, internalized LDLR-LDL-C complex dissociates and LDLR is recycled to the cell surface, whereas LDL-C is directed to lysosomes for degradation. PCSK9 can mediate internalized LDLR-LDL-C complex to degrade, and promote oxLDL-induced inflammation through increasing expression of LOX-1 and TLR4, which increases oxLDL uptake and upregulates inflammatory cytokine expression via activation of ROS and NF-κB