Fig. 7. Pivotal function of SLP76 in RAGE-mediated intracellular signaling in sepsis.

At the onset of sepsis, AGEs are rapidly released and accumulate in the blood. After binding of AGEs with the cell surface receptor RAGE, SLP76 is recruited to the cytosolic tail of RAGE as an adaptor protein to transduce signals from the membrane into the cell, resulting in rapid activation of the p38 MAPK, Erk1/2, and IKKα/β pathways via sequential protein phosphorylation. Activation of downstream kinases results in phosphorylation of transcription factors (TFs) such as NF-κB, thus enhancing the gene transcription of proinflammatory mediators, including TNF, IL-6, CXCL10, HMGB1, etc. The DAMP molecule HMGB1 acts on RAGE, initiating the second wave of protein kinase cascade activation, which generating a positive feedback mechanism to maintain and amplify the proinflammatory response. Overproduction of proinflammatory factors causes tissue damage and finally leads to multiple organ failure and death in mice.