IL-31 Regulation of Immunopathology in Pulmonary Fibrosis

项目摘要 特发性肺纤维化（IPF）影响全球约500万人，并导致 仅在美国就有4万人死亡。IPF的治疗是困难的、不完全的，并且不能治愈。Th 2-细胞因子 极化的T细胞应答被假定介导炎症、成纤维细胞活化、胶原蛋白产生 和进行性纤维化，但对IPF中涉及的特定分子仍存在很大的知识差距， Th 2细胞因子驱动的IPF免疫病理学。白细胞介素-31（IL-31）是一种新发现的细胞因子， 活化的Th 2 T细胞;然而，IL-31在肺部炎症和纤维化中的作用仍然存在， 未知IL-31仅通过由IL-31受体组成的异二聚体受体复合物进行信号传导 α（IL-31 RA）和抑瘤素M受体β（OSMRβ）。我们实验室的初步数据显示 IL-31在IPF肺成熟纤维化病变和博来霉素诱导的小鼠模型中的表达 肺纤维化此外，关键的Th-2细胞因子IL-4和IL-13直接增加了炎症细胞中IL-31 RA的表达。 巨噬细胞和成纤维细胞。重要的是，IL-31信号传导缺陷的小鼠显示出纤维化的减弱， 在博莱霉素诱导的肺纤维化期间改善肺功能。这些发现支持了我们的核心观点。 假设IL-31驱动的信号传导有助于病理性重塑和肺功能 IPF下降。本申请的目的是鉴定IL-31在免疫病理学中的作用。 使用体外和体内模型的IPF。我们的长期目标是了解Th 2细胞因子和IL-10是如何影响免疫系统的。 31-IL-31 RA相互作用可用于IPF的预防和治疗目的。这一假设 将通过追求两个具体目标进行测试：1）确定IL-31在肺纤维化和肺损伤中的作用。 在博来霉素诱导的功能下降中使用遗传模型和相互骨髓细胞转移 肺纤维化;和2）鉴定产生IL-31的T细胞并表征IL-31驱动的转录 网络在IPF。上述目标将确立IL-31信号传导和相关基因网络在 肺纤维化此外，我们将证明IL-31是IPF治疗干预的新靶点。 该方法通过测试IL-4，IL-13和IL-31之间的分子相互作用及其串扰而具有创新性 使用博来霉素诱导的肺纤维化的小鼠模型和基因敲除小鼠。拟议的研究是 意义重大，因为完成这项研究将增加我们对IPF发病机制的了解， 将带来更好的医疗、治疗或预防。

Project Summary Idiopathic Pulmonary Fibrosis (IPF) affects approximately 5 million individuals worldwide and responsible for 40,00 deaths in the USA alone. Treatment for IPF is difficult, incomplete, and not curative. Th2-cytokine polarized T cell responses are postulated to mediate inflammation, fibroblast activation, collagen production and progressive fibrosis in IPF, yet there remains a wide knowledge gap on specific molecules involved in the Th2 cytokine-driven immunopathology of IPF. Interleukin-31 (IL-31) is a newly identified cytokine produced by activated Th2 T cells; however, the role of IL-31 in pulmonary inflammation and fibrosis has remained unknown. IL-31 signals exclusively through a heterodimeric receptor complex consisting of IL-31 receptor alpha (IL-31RA) and oncostatin M receptor beta (OSMRβ). Preliminary data from our laboratory show elevated expression of IL-31, in the mature fibrotic lesions of IPF lungs and mouse model of bleomycin-induced pulmonary fibrosis. Also, key Th-2 cytokines IL-4 and IL-13 directly increased IL-31RA expression in inflamed macrophages and fibroblasts. Importantly, mice deficient in IL-31 signaling show attenuation of fibrosis and improved lung function during bleomycin-induced pulmonary fibrosis. These findings support our central hypothesis that IL-31-driven signaling contributes to the pathological remodelling and lung function decline in IPF. The objective of this application is to identify the role of IL-31 in the immunopathogenesis of IPF using both in vitro and in vivo models. Our long-term goal is to understand how the Th2 cytokines and IL- 31-IL-31RA interactions can be manipulated for preventive and therapeutic purposes in IPF. This hypothesis will be tested by pursuing two specific aims: 1) determine the role of IL-31 in pulmonary fibrosis and lung function decline using genetic models and reciprocal bone marrow cell transfers during bleomycin-induced pulmonary fibrosis; and 2) identify IL-31 producing T cells and characterize IL-31-driven transcriptional networks in IPF. The above aims will establish the role of IL-31 signaling and associated gene networks in pulmonary fibrosis. Further, we will demonstrate that IL-31 is a new target for therapeutic interventions in IPF. The approach is innovative by testing molecular interactions among IL-4, IL-13 and IL-31 and their cross-talk using a mouse model of bleomycin-induced pulmonary fibrosis and knock-out mice. The proposed research is significant, because completion of this study will increase our knowledge of the mechanisms causing IPF and will lead to better medical treatments, cure or prevention.