Th1/Th17 Immune Regulation in Severe Allergic Asthma

项目总结/摘要 这是重新提交的一份题为“Th 1/Th 17免疫调节在严重过敏性哮喘”（1 RO 3 AI 163794 -01），其关注树突状细胞（DCs）介导的Th 1/Th 17免疫调节的机制。 在嗜肺性气道炎症中的反应。重新提交申请的总体目标是获得新的 关于DC的代谢重编程如何促进免疫引发和免疫极化的知识 效应器功能及其如何在严重哮喘气道中诱发和产生炎症环境。 我们从临床和实验证据中知道，呼吸道感染是导致 哮喘加重并促成病情的严重形式，表现为气道粒细胞混合 包括嗜中性粒细胞和嗜酸性粒细胞的炎症。此外，我们认为， 感染的存在也导致刺激先天传感器STING（干扰素基因刺激物）途径， 因为气道中的Th 1/Th 17免疫应答发生偏移。我们最近报道说，不仅激活和 DC的免疫引发功能与细胞代谢状态的深刻改变相关联，而且它 包括由内源性关键代谢物调节的DC特异性应答（Jaiswal等人，Immun. Inflamm. Dis，2019）。新的和令人兴奋的初步数据表明，DC特异性增加免疫应答， 基因1（Irg 1），使顺乌头酸脱羧产生免疫调节代谢物衣康酸，在Th 1/Th 17中 哮喘肺相对于幼稚对照可能有助于解决气道炎症。Irg 1的诱导 与具有屋尘螨（HDM）和STING刺激的DC中的衣康酸产生偶联。结果表明 外源性衣康酸治疗恢复了线粒体呼吸和DC活化CD 4+的能力， T细胞，表明衣康酸对DC免疫启动功能的免疫调节作用。反- 衣康酸盐的炎性作用在体内转化，其中衣康酸盐处理的DC的过继转移减少 气道炎症和T细胞介导的免疫应答。从这些碎片中 我们假设衣康酸在肺DCs中起着独特的调节作用，并且可以被诱导限制 嗜酸性气道炎症。为了验证这一假设，在Aim 1中，我们将首先确定内源性衣康酸是否 是使用Irg 1敲除小鼠发展气道炎症和Th 1/Th 17免疫应答所必需的。在 目的2，我们将确定衣康酸衍生物的外源性治疗是否发挥潜在的抗- 体内炎症特性。总之，这些研究将扩大对如何 Irg 1/衣康酸轴调节DC效应器功能以及是否靶向气道的治疗干预 可降低或消除重度哮喘患者的Th 1/Th 17免疫应答。

Project Summary/Abstract This is the resubmission of a grant entitled “Th1/Th17 Immune Regulation in Severe Allergic Asthma” (1 RO3 AI163794-01) which focuses on the mechanism of dendritic cell (DCs)-mediated regulation of Th1/Th17 immune response in neutrophilic airway inflammation. The overall goal of the resubmission application is to gain new knowledge about how metabolic reprograming of DCs contribute to immune priming and immune-polarizing effector function(s) and how it predisposes and generate the inflammatory milieu in severe asthmatic airways. We know from clinical and experimental evidence that respiratory infections, which are a common trigger for asthma exacerbations and contribute to severe form of the disease, manifested a mixed granulocytic airway inflammation comprising both neutrophils and eosinophils. Moreover, we believe that asthma exacerbations in presence of infections leads to stimulate innate sensor STING (stimulator of interferon genes) pathways, as well as skewing Th1/Th17 immune response in the airways. We recently reported that not only activation and immune-priming function of DCs are coupled to profound alterations of the cellular metabolic state, but also it comprises a DC-specific response modulated by the endogenous key metabolites (Jaiswal et al., Immun. Inflamm. Dis, 2019). New and exciting preliminary data reveal that DC-specific increase of immune responsive gene1 (Irg1), which decarboxylate cis-aconitate to produce immunoregulatory metabolite itaconate, in Th1/Th17 asthmatic lung relative to naïve controls presumably to help resolve airway inflammation. This induction of Irg1 is coupled with itaconate productions in DCs with house dust mite (HDM) and STING stimulations. Results show that exogenous itaconate treatment restored mitochondrial respiration and the capacity of DCs to polarize CD4+ T cells, suggesting an immunoregulatory role of itaconate on DCs immune-priming function(s). The anti- inflammatory effect of itaconate was translated in vivo, where adoptive transfer of itaconate treated DCs reduced airway inflammation and T cell-mediated immune response relative to vehicle-treated DCs. From these pieces of evidence we hypothesize that itaconate plays a distinct regulatory role in lung DCs and can be induced to limit neutrophilic airway inflammation. To test this hypothesis, in Aim1, we will first determine if endogenous itaconate is required for developing airway inflammation and Th1/Th17 immune response using Irg1 knockout mice. In Aim2, we will determine whether exogenous treatment of the itaconate derivative exerts potential anti- inflammatory properties in vivo. Taken together, these studies will expand on the limited knowledge of how Irg1/itaconate axis regulates DC effector function and whether therapeutic interventions targeting the airways could reduce or abolish Th1/Th17 immune response in severe asthma.