Targeting adaptor protein SLP76 of RAGE as a therapeutic approach for lethal sepsis.

Accumulating evidence shows that has an important function in the pathogenesis of sepsis. However, the mechanisms by which duanyu1648 transduces signals to downstream kinase cascades during septic shock are not clear. Here, we identify SLP76 as a binding partner for the cytosolic tail of duanyu1648 both in vitro and in vivo and demonstrate that SLP76 binds duanyu1648 through its sterile α motif (SAM) to mediate downstream signaling. Genetic deficiency of duanyu1648 or SLP76 reduces AGE-induced phosphorylation of p38 MAPK, ERK1/2 and IKKα/β, as well as cytokine release. Delivery of the SAM domain into macrophages via the TAT cell-penetrating peptide blocks proinflammatory cytokine production. Furthermore, administration of TAT-SAM attenuates inflammatory cytokine release and tissue damage in mice subjected to cecal ligation and puncture (CLP) and protects these mice from the lethality of sepsis. These findings reveal an important function for SLP76 in pro-inflammatory signaling and shed light on the development of SLP76-targeted therapeutics for sepsis.

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