1 ± 6.44 versus 38.1 ± 18.64 (P < 0.05) and 40.8 ± 12.91 cells per HPF (P < 0.005); Fig. 6C]. The adaptor protein ASC contributes to immune responses through activation of cysteine protease caspase-1–dependent IL-1β.26 Although under normal conditions ASC-associated inflammasomes

are autorepressed, they become activated by a wide range of pathogen stimuli, including oxidative stress, ischemia, and damage signals. As an endogenous danger signal or alarmin, HMGB1, check details released from activated macrophages/necrotic cells, may bind immune receptors, including TLRs and RAGE, to trigger immune responses.21 This study has identified the essential role of HMGB1 in ASC/caspase-1/IL-1β–dependent inflammatory ASC KO responses in hepatic IRI. Indeed, global decreased sALT levels, depressed local macrophage/neutrophil sequestration, reduced hepatocellular apoptosis, and mitigated proinflammatory cytokine/chemokine

programs in IR-stressed livers. Moreover, ASC deficiency diminished Selleck RAD001 the induction of HMGB1 and alleviated IR-triggered liver damage through negative regulation of TLR4. The molecular mechanisms of ASC/caspase-1/IL-1β signaling for programming an inflammatory phenotype might involve the activation of multiple intercellular pathways. We found that disruption of ASC inhibited HMGB1/TLR4 expression and led to decreased induction of inflammatory mediators; this suggests that ASC/caspase-1/IL-1β plays an important role in triggering local inflammation. In fact, the adaptor ASC was initially believed to exert its effects by bridging the interaction between NLRs and caspase-1 in inflammasome complexes.27 The activation of ASC within inflammasomes leads to the maturation of caspase-1 and the processing of its IL-1β and IL-18

selleck inhibitor substrates. Our in vitro data demonstrate that ASC deficiency decreased caspase-1 activity and IL-1β/IL-18 production in LPS-stimulated BMMs, and this implies a role for ASC in caspase-1/IL-1β–mediated inflammation. Although the ASC/caspase-1/IL-1β axis is essential for the initiation of an inflammatory response, the molecular pathways involved in crosstalk with HMGB1 have not been elucidated. Our data demonstrate that the treatment of ASC KO mice with rHMGB1 increased IR-induced hepatocellular damage, whereas the disruption of ASC without exogenous rHMGB1 prevented hepatic inflammatory development. These results are consistent with the ability of endogenous HMGB1 to promote liver IR damage19 and suggest that HMGB1 might have a distinct role during ASC/IL-1β–mediated inflammation in hepatic IRI. As an intracellular protein, HMGB1 translocates to the nucleus, where it binds DNA to regulate gene transcription.28 However, extracellular HMGB1 has been shown to act as a cytokine mediator in response to inflammatory stimuli due to infection,15 whereas HMGB1 promotes TLR4-mediated inflammation in hepatic IRI.