title: ASC/caspase-1/IL-1β signaling triggers inflammatory responses by promoting HMGB1 induction in liver ischemia/reperfusion injury.
abstract: Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an adaptor protein for inflammasome receptors, is essential for inducing caspase-1 activation and the consequent secretion of interleukin-1β (IL-1β), which is associated with local inflammation during liver ischemia/reperfusion injury (IRI). However, little is known about the mechanisms by which the 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. With a partial lobar liver warm ischemia (90 minutes) model, ASC-deficient and wild-type mice (C57BL/6) were sacrificed at 6 hours of reperfusion. Separate animal cohorts were treated with an anti-IL-1β antibody or control immunoglobulin G (10 mg/kg/day intraperitoneally). We found that ASC deficiency inhibited caspase-1/IL-1β signaling and led to protection against liver ischemia/reperfusion (IR) damage, local enhancement of antiapoptotic functions, and down-regulation of high mobility group box 1 (HMGB1)-mediated, toll-like receptor 4 (TLR4)-driven inflammation. Interestingly, the treatment of ASC-deficient mice with recombinant HMGB1 re-created liver IRI. Moreover, neutralization of IL-1β ameliorated the hepatocellular damage by inhibiting nuclear factor kappa B (NF-κB)/cyclooxygenase 2 signaling in IR-stressed livers. In parallel in vitro studies, the knockout of ASC in lipopolysaccharide-stimulated bone marrow-derived macrophages depressed HMGB1 activity via the p38 mitogen-activated protein kinase pathway and led to the inhibition of TLR4/NF-κB and ultimately the depression of proinflammatory cytokine programs.
  
  
  CONCLUSIONS
  ASC-mediated caspase-1/IL-1β signaling promotes HMGB1 to produce a TLR4-dependent inflammatory phenotype and leads to hepatocellular injury. Hence, ASC/caspase-1/IL-1β signaling mediates the inflammatory response by triggering HMGB1 induction in hepatic IRI. Our findings provide a rationale for a novel therapeutic strategy for managing liver injury due to IR.
authors: Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplantation Center, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.
authors: Naoko
authors: N
authors: Kamo
authors: Bibo
authors: B
authors: Ke
authors: Amir A
authors: AA
authors: Ghaffari
authors: Xiu-da
authors: XD
authors: Shen
authors: Ronald W
authors: RW
authors: Busuttil
authors: Genhong
authors: G
authors: Cheng
authors: Jerzy W
authors: JW
authors: Kupiec-Weglinski
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000502:physiology*; D024243:HMGB1 Protein / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000502:physiology*; D008099:Liver / Q000293:injuries; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000276:immunology* / Q000517:prevention & control; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D053583:Interleukin-1beta; C498534:Pycard protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D020170:Caspase 1