The ASC/Caspase-1/IL-1β signaling triggers inflammatory responses by promoting HMGB1 induction in liver ischemia-reperfusion injury

摘要

Apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), an adaptor protein for inflammasome receptors, is essential for inducing the caspase-1 activaton and the consequent secretion of IL-1β, which associates with local inflammation during liver ischemia/reperfusion injury (IRI). However, little is known on mechanisms by which ASC/Caspase-1/IL-1β axis exerts its function in hepatic IRI. This study was designed to explore the functional roles and molecular mechanisms of ASC/Caspase-1/IL-1β signaling in the regulation of inflammatory responses in vitro and in vivo. Using a partial lobar liver warm ischemia (90min) model, ASC-deficient and WT mice (C57BL/6) were sacrificed at 6h of reperfusion. Separate animal cohorts were treated with anti-IL-1β Ab or control IgG (10mg/kg, day −1, i.p.). We found that ASC deficiency inhibited Caspase-1/IL-1β signaling, leading to the protection against liver IR-damage, local enhancement of antiapoptotic functions, and downregulation of HMGB1-mediated TLR4-driven inflammation. Interestingly, treatment of ASC-deficient mice with rHMGB1 recreated liver IRI. Moreover, neutralization of IL-1β ameliorated the hepatocellular damage by inhibiting NF-κB/COX2 signaling in IR-stressed livers. In parallel in vitro studies, knockout of ASC in LPS-stimulated bone marrow derived-macrophages depressed HMGB1 activity via p38 MAPK pathway, leading to the inhibition of TLR4/NF-κB, and ultimate depression of proinflammatory cytokine programs. Conclusion: ASC-mediated Caspase-1/IL-1β signaling promotes HMGB1 to produce TLR4-dependent inflammatory phenotype, leading to hepatocellular injury. Hence, the ASC/Caspase-1/IL-1β signaling mediates inflammatory response by triggering HMGB1 induction in hepatic IRI. Our findings provide the rationale for a novel therapeutic strategy to manage liver injury due to IR.