Mechanisms Regulating Innate Immune Responses

描述（由申请方提供）：宿主与微生物之间的相互作用在粘膜表面至关重要。这些相互作用中的失调可导致肠道炎性疾病，例如炎性肠病（IBD）。对微生物的识别和应答最初由模式识别受体（PRR）介导。PRR应答导致细胞因子的分泌和细胞活化，以及微生物清除。这些结果之间的平衡影响炎症性疾病和感染性疾病之间的易感性。我们的长期目标是了解IBD发病机制，从而最终改善人类IBD的管理和治疗。IRF 5的多态性与多种免疫介导的疾病相关，包括IBD。我们最近发现，IRF 5是整个人群中PRR启动的信号传导和髓源性细胞的细胞因子个体间差异的关键决定因素; IRF 5疾病风险多态性的携带者响应于一系列PRR刺激分泌高水平的细胞因子。尽管IRF 5在调节人骨髓来源的PRR诱导的细胞因子的个体间变异中具有重要性，但其有助于人细胞中PRR引发的信号传导途径的机制尚未明确（SA 1）。我们假设IRF 5通过与其在细胞质和细胞核中的定位相关的机制组合来调节人骨髓细胞中PRR引发的信号传导和结果，最终促成其在调节PRR中的广泛和关键作用。将探索IRF在介导相关细胞亚群（例如M1 vs. M2）分化中的作用（SA 2a）。 此外，IRF 5如何影响肠道常驻微生物和致病微生物的清除尚不清楚（SA 2b）。重要的是，IRF 5在体内促进IBD发病机制的机制尚未得到研究（SA 3）。我们将整合原代人类细胞的研究与小鼠体内研究，以剖析IRF 5对IBD发病机制的贡献。我们假设IRF 5将有助于体内肠道免疫稳态所必需的多种免疫细胞亚群的功能，并且尽管它可能有助于结肠炎的炎症结果，但它对于调节肠道病原体是必不可少的。

DESCRIPTION (provided by applicant): The interplay between host:microbial interactions is critical at mucosal surfaces. Dysregulation in these interactions can lead to intestinal inflammatory diseases, such as inflammatory bowel disease (IBD). The recognition and response to microbes is initially mediated by pattern recognition receptors (PRR). PRR responses lead to secretion of cytokines and cellular activation, as well as microbial clearance. The balance between these outcomes influences susceptibility between inflammatory diseases and infectious diseases. Our long-term goal is to understand the mechanisms mediating IBD pathogenesis, thereby ultimately improving the management and therapy of human IBD. Polymorphisms in IRF5 are associated with a wide-range of immune-mediated diseases, included IBD. We recently found that IRF5 is a critical determinant of the inter-individual variation in PRR-initiated signaling and cytokines from myeloid-derived cells across the population; carriers of the IRF5 disease risk polymorphisms secrete high levels of cytokines in response to a range of PRR stimuli. Despite the importance of IRF5 in regulating inter-individual variation in human myeloid-derived PRR-induced cytokines, the mechanism through which it contributes to PRR-initiated signaling pathways in human cells is not well defined (SA 1). We hypothesize that IRF5 regulates PRR- initiated signaling and outcomes in human myeloid cells through a combination of mechanisms associated with its localization in both the cytoplasm and nucleus, ultimately contributing to its broad and critical role in regulating PRRs. The role of IRF in mediating differentiation of related cellular subsets (e.g. M1 vs. M2) will be explored (SA 2a). Moreover, how IRF5 affects clearance of both resident and pathogenic intestinal microbes is not known (SA 2b). Importantly, the mechanism through which IRF5 contributes to IBD pathogenesis in vivo has not been examined (SA 3). We will integrate studies in primary human cells with in vivo mouse studies to dissect IRF5 contributions to IBD pathogenesis. We hypothesize that IRF5 will contribute to functions in multiple immune cell subsets essential in intestinal immune homeostasis in vivo, and that although it may contribute to inflammatory outcomes in colitis, it is essential for regulating intestinal pathogens.