Feedback regulation of innate immune signaling at mucosal surfaces

描述（由申请人提供）：作为人类，我们不断暴露于病原体。我们的先天免疫系统必须能够区分致病性和非致病性生物体，并且它必须能够定制免疫反应来对致病性生物体作出反应。这个问题在粘膜表面尤其严重，因为身体的表面细胞与细菌、真菌和病毒直接接触。许多炎症性疾病，包括克罗恩病，在病原体被根除后，当最初的先天免疫反应没有充分下调时，就会在这些粘膜表面启动。在这项资助中，我们研究了在粘膜表面控制这种下调的机制。我们发现一种关键的抗炎蛋白A20被NF-？B信号通路（IKK2）。我们绘制了磷酸化位点，并表明这是A20抑制活性的必要条件。我们产生了针对这个位点的磷酸化特异性抗体，我们已经证明这种磷酸化在体内对许多炎症刺激的反应中发生。我们的中心假设是，ikk依赖性的A20磷酸化导致了一种新的反馈机制来抑制NF-？B反应使得粘膜表面不会发生过多的炎症。IKK磷酸化A20的失败可能导致炎症病理，如克罗恩病。这项拨款旨在验证这一假设。黏膜免疫调节对各种病毒、细菌和真菌病原体的初始免疫反应。粘膜免疫失调是多种炎症性疾病的起始事件，包括炎症性肠病、哮喘、肾盂肾炎和一些原发性免疫缺陷。了解这种失调是如何发生的，对于理解慢性炎症性疾病的病理生理学和预防暴露于病原体后发生这种失调都有意义。

DESCRIPTION (provided by applicant): As humans, we are continuously exposed to pathogens. Our innate immune system must be able to differentiate pathogenic from nonpathogenic organisms, and it must be able to tailor an immune response to respond to that pathogenic organism. This problem is particularly acute at mucosal surfaces, an area of the body in which the surface cells are in direct contact with bacteria, fungi and viruses. A number of inflammatory disorders, including Crohn's Disease, are initiated at these mucosal surfaces when the initial innate immune response is not adequately down-regulated after the pathogen is eradicated. In this grant, we study the mechanisms that control this down-regulation at mucosal surfaces. We have found that a key anti-inflammatory protein, A20, is phosphorylated and activated by the central kinase in the NF-?B signaling pathway (IKK2). We mapped the site of phosphorylation and have shown that it is required for full A20 inhibitory activity. We generated a phospho-specific antibody against this site, and we have shown that this phosphorylation occurs in vivo in response to a number of inflammatory stimuli. Our central hypothesis is that the IKK-dependent phosphorylation of A20 leads to a novel feedback mechanism to inhibit the NF-?B response such that too much inflammation does not occur at mucosal surfaces. Failure of IKK to phosphorylate A20 may lead to inflammatory pathology such as that seen in Crohn's Disease. This grant is designed to test this hypothesis. Mucosal immunity regulates the initial immune response to a variety of viral, bacterial and fungal pathogens. Dysregulation of mucosal immunity is an initiating event in a variety of inflammatory disorders including Inflammatory Bowel Disease, Asthma, Pyelonephritis and a number of primary immunodeficiencies. Understanding how this dysregulation occurs will have relevance both for understanding the pathophysiology of chronic inflammatory diseases and for preventing this dysregulation from occurring after exposure to pathogens. PUBLIC HEALTH RELEVANCE Mucosal immunity regulates the initial immune response to a variety of viral, bacterial and fungal pathogens. Dysregulation of mucosal immunity is an initiating event in a variety of inflammatory disorders including Inflammatory Bowel Disease, Asthma, Pyelonephritis, and a number of primary immunodeficiencies. Understanding how this dysregulation occurs will have relevance both for understanding the pathophysiology of chronic inflammatory diseases and for preventing this dysregulation from occurring after exposure to pathogens.