Project 4: Hemorrhagic Shock Regulation of Inflammasome

出血性休克（HS），作为严重创伤的结果，促进全身炎症反应的发展， 免疫反应综合征（SIRS）通过激活和启动先天免疫系统， 炎症反应通过目前尚不清楚的机制。HS诱导的促炎细胞因子分泌 在SIRS的发展中起着重要作用。白细胞介素-l β（IL-1 β）是一种重要的促细胞因子， 炎症介质，其加工和分泌在HS、创伤和 感染研究表明，炎性小体是一种多蛋白复合物，是一个分子平台， 炎性半胱天冬酶的活化以及前IL-1 β和IL-18的加工。我们的初步研究表明 揭示了HS不仅诱导肺泡巨噬细胞（AM）分泌IL-1 β， AM对细菌产物LPS和肽聚糖刺激的反应性增强的IL-1 β释放 (PGN)通过炎性小体/caspase-1依赖机制，表明HS的重要调节作用 炎症体激活此外，我们观察到Toll样受体（TLR）2信号，这是上升， 由LPS/TLR 4信号调节并由HS增强，触发AM中的pro-IL-1 β加工，而不依赖于 “典型的”钾外流途径，这表明TLR 2信号转导是HS调节的一种新途径， 炎性小体激活。基于这些观察结果，我们假设I）炎性小体是一个主要靶点 HS在发展创伤后SIRS中的作用; II）HS诱导的炎性小体激活的潜在机制 是多样的，其中包括“激活”和“启动”机制; III）TLRs的串扰作为一种新的 介导HS引发的前IL-1 β加工的机制。我们将从三个方面来探讨这些假设 相关目的：1）明确HS损伤对炎性小体细胞活化的危险信号; 2） 以确定介导炎性小体的HS活化的细胞内信号传导;以及3）确定炎症小体的HS活化的细胞内信号传导。 通过上调TLR 2信号传导的HS引发的炎性体活化的机制。为了实现所述 目标，多学科模型，如体内小鼠HS模型和基因过表达或敲除 嵌合小鼠模型以及离体AM-中性粒细胞共培养系统将应用于研究。 相关性（参见说明）： IL-1 β在HS诱导的炎症反应中起着重要而广泛的作用，而炎性小体在炎症反应中处于中心地位。 控制IL-1 β过程。深入了解HS对炎性小体的调控机制将为我们提供 HS后SIRS预防和治疗干预的新靶点。从更广泛的意义上说，这项研究将 有助于更好地了解先天免疫发挥作用的其他人类疾病。

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.