The Non-Inflammasome NLRs in Immunity and Host defense

 描述（由申请人提供）：NOD样受体（NLR）是参与响应感染和细胞应激的炎症信号传导调节的细胞内传感器分子家族。最近的研究揭示了NLR介导的炎症在多种人类自身免疫性和炎症性疾病中的关键作用。迄今为止，绝大多数NLR已被定义为先天免疫细胞中炎症信号传导的激活剂。例如，原型NLR成员NOD 1和NOD 2响应于它们对细菌肽聚糖片段的直接识别而启动促炎性NF-κB和MAPK信号传导。还描述了多个NLR通过协调炎性体复合物的组装来促进促炎细胞因子IL-1β和IL-18的活化和分泌。相反，一些NLR，如NLRP 6，NLRP 12，NLRC 3和NLRX 1，负调控炎症信号传导。然而，这类新的抑制性NLR直接抑制炎症的细胞和分子机制尚不清楚。NLRP 12的错义突变与人类的炎症性疾病有关，但这些病理的生化机制和途径仍不清楚。我们实验室最近的工作表明，NLRP 12是NF-κB信号转导的关键负调节因子。重要的是，炎症和免疫病理学并不完全限于炎症和自身免疫性疾病。先天免疫和适应性免疫的失调也可导致传染病发病率和死亡率方面的显著差异。在这方面，NLRP 12在病毒感染和产生适应性免疫应答中的作用尚未研究。因此，该项目具有重要意义，因为它将导致识别参与宿主的关键免疫机制， 防御和炎症控制机制依赖于NLRP 12调节炎症。我们将通过使用甲型流感病毒来研究这些机制。

 DESCRIPTION (provided by applicant): NOD-like receptors (NLRs) are a family of intracellular sensor molecules involved in the regulation of inflammatory signaling in response to infection and cellular stress. Recent studies have revealed pivotal roles for NLR-mediated inflammation in a spectrum of diverse human autoimmune and inflammatory disorders. The vast majority of NLRs to date have been defined as activators of inflammatory signaling in innate immune cells. For instance, the prototypical NLR members, NOD1 and NOD2, initiate proinflammatory NF-κB and MAPK signaling in response to their direct recognition of bacterial peptidoglycan fragments. Multiple NLRs have also been described to promote the activation and secretion of the proinflammatory cytokines IL-1β and IL-18 by coordinating the assembly of the inflammasome complex. In contrast, some NLRs, such as NLRP6, NLRP12, NLRC3 and NLRX1, negatively regulate inflammatory signaling. However, the cellular and molecular mechanisms that direct the suppression of inflammation by this new class of inhibitory NLRs are not known. Missense mutations in NLRP12 are associated with inflammatory diseases in humans, but the biochemical mechanisms and pathways underlying these pathologies remain unclear. Recent work from our lab demonstrates that NLRP12 functions as a key negative regulator of NF-κB signaling. Importantly, inflammation and immunopathology are not exclusively restricted to inflammatory and autoimmune diseases. The dysregulation of innate and adaptive immunity can also result in striking differences with regard to morbidity and mortality during infectious disease. In this regard, NLRP12's role in viral infection and generation of adaptive immune responses has not been investigated. Therefore, this project is highly significant, as it will lead to the identification of key immune mechanisms involved in host defense and inflammatory control mechanisms dependent on NLRP12 that regulate inflammation. We will examine these mechanisms through the use of influenza A virus.