Regulation of Caspase-1 Signaling and Inflammation by the P2X7 ATP Receptor

P2X7受体(P2X7R)是在免疫效应细胞中表达的细胞外ATP门控离子通道，如 作为巨噬细胞，在微生物感染或感染的早期阶段执行关键的保护反应 急性组织创伤。由于它存在于所有细胞中，三磷酸腺苷可以在 组织损伤和微生物入侵的部位。刺激P2X7R迅速触发血管内皮细胞分泌 促炎症细胞因子白介素1β(IL-1β)通过激活caspase-1，一种调节 炎症和细胞死亡。因为caspase-1信号是自我放大的，而且可逆性很差，所以它必须是 严格维持在非活跃状态，直到免疫效应细胞整合多个刺激 在微生物感染或组织损伤的部位产生。这些刺激包括井- 病原体相关分子模式(PAMP)配体的特征Toll样受体(TLR) 由入侵的微生物释放。我们认为，P2X7R的激活提供了一种重要的佐剂 TLRs和PAMPs对caspase-1信号通路的作用。我们假设，P2X7R&GT； Caspase-1和IL-1β级联反应涉及细胞间和细胞间对P2X7R信号的协同调节 细胞内水平。目标1是定义将P2X7R偶联到 IL-1β背后的caspase-1炎症体复合体的组装、激活和输出 加工和分泌。目的2是确定P2X7R调节的信号通路在激活中的作用 在体外感染小鼠巨噬细胞过程中caspase-1/IL-1β的输出 李斯特菌和沙门氏菌的致病菌株。目标3是定义细胞外依赖的ATP的作用 P2X7R/caspase-1/ll_-1bet.a级联激活与ATP非依赖机制的比较 强调细胞外NAD和胞外-ADP-核糖基转移酶的调节作用，并通过 与位于感染和炎症部位的受损宿主细胞相互作用。这些P2X7R- 调节通路(激活caspase-1和分泌IL-1β)与多个 炎症性和自身免疫性疾病，包括周期性发热综合征、克罗恩病和 风湿性关节炎，以及包括沙门氏菌、志贺氏菌、 李斯特菌和炭疽杆菌。

P2X7 receptors (P2X7R) are extracellular ATP-gated ion channels expressed in immune effector cells, such as macrophages, that carry out critical protective responses during the early phases of microbial infection or acute tissue trauma. Given its presence in all cells, ATP can be released into extracellular compartments at sites of tissue damage and microbial invasion. Stimulation of P2X7R rapidly triggers secretion of the proinflammatory cytokine, interleukin-1beta (IL-1beta) via activation of caspase-1, a protease that regulates inflammation and cell death. Because caspase-1 signaling is self-amplifying and poorly reversible, it must be stringently maintained in an inactive state until immune effector cells integrate multiple stimuli that are generated within the locus of microbial infection or tissue damage. These stimuli include the well- characterized Toll-like receptors (TLR) for Pathogen-Associated Molecular Pattern (PAMP) ligands that are released by invading microbes. We propose that the activation of P2X7R provides an important adjuvant action to the caspase-1 signaling cascades elicited by TLRs and PAMPs. We hypothesize that the P2X7R > caspase-1 > IL-1beta cascade involves synergistic regulation of P2X7R signaling at both the intercellular and intracellular levels. Aim 1 is to define the intracellular signal transduction mechanisms that couple P2X7R to the assembly, activation, and export of the caspase-1 inflammasome complexes which underlie IL-1beta processing and secretion. Aim 2 is to define the role of P2X7R-regulated signaling pathways in activation and export of caspase-1/ IL-1beta during in vitro infection of murine macrophages by non-pathogenic versus pathogenic strains of Listeria and Salmonella. Aim 3 is to define the roles of extracellular ATP-dependent versus ATP-independent mechanisms in the activation of the P2X7R/ caspase-1/ ll_-1bet.a cascade with emphasis on the regulatory effects of extracellular NAD and ecto-ADP-ribosyltransferases, and by interactions with damaged host cells that populate sites of infection and inflammation. These P2X7R- regulated pathways (activation of caspase-1 and secretion of IL-1beta) have been linked to multiple inflammatory and autoimmune diseases including the Periodic Fever Syndromes, Crohn's disease, and rheumatoid arthritis, as well as the pathogenicity of disease-causing bacteria including Salmonella, Shigella, Listeria, and Anthrax.