The
toll-like receptor 5 (TLR5) agonist,
CBLB502/
Entolimod, is a
peptide derived from bacterial
flagellin and has been shown to protect against radiation-induced tissue damage in animal models. Here we investigated the protective mechanism of
CBLB502 in the liver using models of
ischemia-reperfusion injury and
concanavalin A (ConA) induced immuno-
hepatitis. We report that pretreatment of mice with
CBLB502 provoked a concomitant activation of NF-κB and STAT3 signaling in the liver and reduced hepatic damage in both models. To understand the underlying mechanism, we screened for
cytokines in the serum of
CBLB502 treated animals and detected high levels of
IL-22. There was no transcriptional upregulation of
IL-22 in the liver, rather it was found in extrahepatic tissues, mainly the colon, mesenteric lymph nodes (MLN), and spleen.
RNA-seq analysis on isolated hepatocytes demonstrated that the concomitant activation of NF-κB signaling by
CBLB502 and STAT3 signaling by
IL-22 produced a synergistic cytoprotective transcriptional signature. In
IL-22 knockout mice, the loss of
IL-22 resulted in a decrease of hepatic STAT3 activation, a reduction in the cytoprotective signature, and a loss of hepatoprotection following
ischemia-reperfusion-induced liver injury. Taken together, these findings suggest that
CBLB502 protects the liver by increasing hepatocyte resistance to acute liver injury through the cooperation of TLR5-NF-κB and IL-22-STAT3 signaling pathways.