Fig. 2

The release of HMGB1 protein and HMGB1 signaling pathways. The release mechanism of HMGB1 into the extracellular environment includes passive release and active release. In response to infections and injuries, HMGB1 can translocate outside the cell by passive release from damaged or necrotic cells or active secretion from activated immune cells. The interaction of HMGB1 with RAGE, TLR2, TLR4, and TLR9 transduces cellular signals through a common pathway that induces the NF-κB pathway. Then, activated NF-κB translocates to the nucleus and interacts with DNA as a p65/p50 heterodimer. HMGB1 also interacts with CXCL12/CXCR4 to activate the NF-κB pathway and induce chemotaxis and recruitment of inflammatory cells. The activated NF-κB pathway promotes nuclear HMGB1 acetylation and secretion. HMGB1 binding to RAGE could activate PPAR-γ, which could inhibit HMGB1-RAGE activation. The interaction of HMGB1 and TIM-3 induces the secretion of VEGF to promote tumor angiogenesis