Fig. 3.

HMGB1 binding to receptors and activating signal transduction pathway. Interaction of HMGB1 with RAGE, TLR2, TLR4, and TLR9 transduce cellular signals through a common pathway that leads to activation of NF-κB. HMGB1 interaction with LPS, LTA, and CpG enhances TLR4-, TLR2-, and TLR9-mediated signaling, respectively, and further leads to downstream signaling of NF-κB activation and proinflammatory cytokine production. Activated NF-κB gets released from IκB translocates to the nucleus and binds to the DNA in the most abundant form of NF-κB, the p65/p50 heterodimer form. HMGB1 also interacts with CXCL12, which binds to CXCR4 and induces chemotaxis and recruitment of inflammatory cells.