Project 4: Hemorrhagic Shock Regulation of Inflammasome

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Hemorrhagic shock (HS), as a result of major trauma, promotes the development of systemic inflammatory response syndrome (SIRS) by activating and priming the innate immune system for an exaggerated inflammatory response through as of yet unclear mechanisms. HS-induced pro-inflammatory cytokines secretion plays an important role in the development of SIRS. Interleukin-lbeta (IL-lbeta) is one of the key pro¿ inflammatory mediators, and its processing and secretion is tightly controlled in the settings of HS, trauma, and infection. It has been shown that inflammasome, a multiprotein complex, is a molecular platform triggering activation of inflammatory caspase and processing of pro-IL-lbeta and IL-18. Our preliminary studies have revealed that HS not only induces IL-lbeta secretion from alveolar macrophages (AM) but also primes for an enhanced IL-lbeta release from AM in response to stimulations of bacterial products LPS and peptidoglycan (PGN) through inflammasome/caspase-1-dependent mechanisms, suggesting an important regulatory role of HS in inflammasome activation. Furthermore, we observed that Toll-like receptor (TLR)2 signaling, which was up¿ regulated by LPS/TLR4 signal and enhanced by HS, triggers pro-lL-lbeta processing in AM independent of the "typical" potassium efflux pathway, suggesting that TLR2 signaling is a novel pathway in HS regulation of inflammasome activation. Based on these observations, we hypothesize that I) inflammasome is a major target of HS in developing post-traumatic SIRS; II) the mechanisms underlying HS-induced inflammasome activation are diverse, which include "activating" and "priming" mechanisms; III) cross-talk of TLRs serves as a novel mechanism mediating HS-primed pro-IL-lbeta processing. We will pursue these hypotheses in three interrelated Aims: 1) to define the danger signal that transduces HS insult to cell activation of inflammasome; 2) to determine the intracellular signaling that mediates HS activation of inflammasome; and 3) to determine the mechanism of HS-primed activation of inflammasome by upregulated TLR2 signaling. To achieve the stated goals, multidisciplinary models, such as in vivo mouse HS model and gene overexpression or knockdown chimeric mouse model, as well as ex vivo AM-neutrophil co-culture system, will be applied to the studies. RELEVANCE (See instructions): lL-1beta plays important and broad roles in HS-induced inflammation, and inflammasome sits at the center in controlling IL-1 beta process. An insight of the mechanisms of HS regulation of inflammasome will provide us novel target for preventive and therapeutic interventions of post-HS SIRS. In a broader sense the study will contribute to a greater understanding of other human diseases where innate immunity plays a role.