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、不完整的，而且不能治愈。Th2细胞因子 极化的T细胞反应被认为是介导炎症、成纤维细胞激活和胶原产生的媒介 和进行性纤维化，但对参与IPF的特定分子仍有很大的认识差距 Th2细胞因子驱动的特发性肺纤维化免疫病理机制。白介素31(IL-31)是新近发现的一种细胞因子。 活化的Th2T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信号完全通过由IL-31受体组成的异二聚体受体复合体 α(IL-31RA)和肿瘤抑素M受体β(OSMRβ)。我们实验室的初步数据显示 IL-31在IPF肺成熟性纤维化病变及博莱霉素性小鼠模型中的表达 肺纤维化。此外，关键的Th-2细胞因子IL-4和IL-13直接增加炎症组织中IL-31RA的表达 巨噬细胞和成纤维细胞。重要的是，IL-31信号缺陷的小鼠表现出纤维化的减弱和 改善博莱霉素性肺纤维化期间的肺功能。这些发现支持我们的中心 假设IL-31驱动的信号转导有助于病理重塑和肺功能 IPF下降。本应用的目的是确定IL-31在慢性粒细胞白血病免疫发病机制中的作用。 采用体外和体内两种IPF模型。我们的长期目标是了解Th2细胞因子和IL-2是如何 31-IL-31RA的相互作用可用于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在肺纤维化和肺组织中的作用 用遗传模型研究博莱霉素诱导的功能减退和骨髓细胞的相互转移 肺纤维化；2)鉴定产生IL-31的T细胞并鉴定IL-31驱动的转录 IPF中的网络。上述目标将确立IL-31信号和相关基因网络在 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以及它们之间的串扰来进行创新 采用博莱霉素诱导的小鼠肺纤维化模型和基因敲除小鼠。拟议的研究是 因为这项研究的完成将增加我们对IPF和IPF的机制的了解 将带来更好的医疗、治愈或预防。

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.