Mechanisms Regulating Innate Immune Responses

描述（由申请人提供）：宿主与微生物之间的相互作用在粘膜表面至关重要。这些相互作用的失调可导致肠道炎症性疾病，如炎症性肠病（IBD）。对微生物的识别和应答最初是由模式识别受体（PRR）介导的。PRR反应导致细胞因子的分泌和细胞激活，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介导IBD发病机制，从而最终改善人类IBD的管理和治疗。IRF5的多态性与包括IBD在内的多种免疫介导疾病有关。我们最近发现，IRF5是prr启动的信号和细胞因子在整个人群中个体间变异的关键决定因素；IRF5疾病风险多态性的携带者在一系列PRR刺激下分泌高水平的细胞因子。尽管IRF5在调节人类髓源性prr诱导的细胞因子的个体间变异方面具有重要意义，但它在人类细胞中参与prr启动的信号通路的机制尚不明确（SA 1）。我们假设IRF5通过其在细胞质和细胞核中的定位相关的机制组合来调节人类髓细胞中PRR启动的信号和结果，最终促成其在调节PRR中广泛而关键的作用。将探讨IRF在介导相关细胞亚群（例如M1与M2）分化中的作用（SA 2a）。

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.