Interplay between Type I IFN and TGF-beta signaling in systemic sclerosis

I 型 IFN 和 TGF-β 信号在系统性硬化症中的相互作用

• 批准号: 8444432
• 负责人: Giuseppina Alessandra Farina
• 金额: $ 7.78万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444432
• 关键词: Autoimmune Diseases; Biological; Biological Process; Cells; Cicatrix; Clinical; Clinical Trials; Cutaneous; Dermal; Diffuse; Disease; Equilibrium; Fibroblasts; Fibrosis; Gastrointestinal tract structure; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Goals; Grant; Human; Immune; Immune System Diseases; Immune response; Impairment; Inflammation; Inflammatory; Interferon Receptor; Interferon Type I; Interferon-beta; Interferons; Kidney; Ligands; Link; Lung; MADH7 gene; Measures; Mediating; Mediator of activation protein; Medicine; Messenger RNA; Mus; NF-kappa B; Natural Immunity; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Phosphorylation; Physiological; Play; Production; Receptor Activation; Regulatory Pathway; Risk; Role; STAT4 gene; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Skin; Systemic Scleroderma; Testing; Transforming Growth Factor beta; Wild Type Mouse; base; design; human TLR3 protein; immune activation; in vivo; inhibitor/antagonist; innovation; interferon alpha receptor; novel; programs; receptor; research study; response; therapeutic target

DESCRIPTION (provided by applicant): Although it is generally agreed that transforming growth factor-beta (TGF¿) plays a central role in sustaining fibrosis in systemic sclerosis (SSc), the triggers of TGF¿, TGF¿ activation and TGF¿ intracellular signaling are still unknown. The goal of this grant is to understand how TGF¿ signal activation is up-regulated in SSc focusing on the link between innate immunity, inflammation and fibrosis. New emerging evidence points to the importance of innate immunity and interferons (IFNs) in many autoimmune diseases including SSc, and we found that in addition to upregulated TGF¿ gene expression SSc skin and peripheral blood mononuclear cells (PBMC) also show upregulated IFN gene expression. Interestingly more recently we found that polyIC, a toll like receptor 3 (TLR3) ligand, activates human fibroblasts (fb), inducing not only genes known to be regulated by IFNs but also genes that are induced by TGF¿, suggesting that TGF¿ activation and then fibrosis is regulated by the innate immune response. Thus this application proposes to investigate how innate immune activation regulates inflammation and scarring through cross talk between IFN¿/¿and TGF¿. One of the most exciting of our preliminary results is that polyIC and IFN¿ both induce Smad1 phosphorylation, indicating crossactivation of TGF¿ signaling by IFN¿/¿. In addition we unexpectedly discovered that IFN¿ a receptor 2 (IFNAR2) in mice deficient of the IFN¿ receptor 1 (IFNAR1 -/-) activates a "non classical" IFN¿/¿ pathway, and that this pathway may be involved in entirely new biological functions such as controlling the induction of TGF¿ signaling components. In the first aim, proposed experiments will examine the mechanism controlling the physiologic balance between the induction and suppression of the pro-inflammatory program through cross talk between IFN and TGF¿ in fb from wild type (WT) mice, studying Smad1/2/3 expression and phosphorylation, IRF7 and Smad7 gene expression. Then we will investigate the consequences of aberrant IFN signaling that promote novel cross talk between IFN and TGF¿, and causing the modified equilibrium in TLR activation promoting the profibrotic phenotype in fb from IFNAR1-/- mice. Aim 2 will explore whether impairment of IFN¿/¿ signaling might underlie the pro-fibrotic phenotype that characterizes SSc fb, as we observed in IFNAR1 -/- fb. Experiments in this aim will test the effect of IFN¿ and polyIC on TGF¿ signaling components and the functioning of INF¿/¿ signaling in SSc compared to normal fb. Finally we will examine the in vivo expression of selected IFN¿/¿ and TGF¿ mediators IRF7 and Smad7, in SSc and control skin. Together, these results should significantly extend our understanding of the role of innate immune activation, IFNs and TGF¿ in dermal fibrosis, enlightening a new standpoint of SSc pathogenesis that IFN¿/¿ impairment might be the primary cause of uncontrolled TGF¿ activation. In addition the new finding of IFNAR2 function in controlling activation of TGF¿ signaling, add a novel biological response to the complexity of IFN-mediated signaling potentially influencing the clinical use of therapeutics targeting IFNs not only in SSc but also in other diseases.

描述（由申请人提供）：虽然人们普遍认为转化生长因子- β (TGF - β)在系统性硬化症（SSc）中维持纤维化中起核心作用，但TGF -、TGF -激活和TGF -胞内信号传导的触发机制尚不清楚。这项资助的目的是了解TGF¿信号激活如何在SSc中上调，重点关注先天免疫、炎症和纤维化之间的联系。新出现的证据指出先天免疫和干扰素（IFNs）在包括SSc在内的许多自身免疫性疾病中的重要性，我们发现除了TGF¿基因表达上调外，SSc皮肤和外周血单核细胞（PBMC）也表现出IFN基因表达上调。有趣的是，最近我们发现polyIC，一种toll样受体3 （TLR3）配体，激活人成纤维细胞（fb），不仅诱导已知由ifn调节的基因，还诱导TGF诱导的基因，表明TGF激活然后纤维化是由先天免疫反应调节的。因此，本应用建议研究先天免疫激活如何通过IFN和TGF之间的串扰调节炎症和瘢痕形成。我们最令人兴奋的初步结果之一是polyIC和IFN¿都诱导Smad1磷酸化，表明IFN¿/¿交叉激活TGF -信号传导。此外，我们意外地发现，在缺乏IFN受体1 （IFNAR1 -/-）的小鼠中，IFN受体2 （IFNAR2）激活了一条“非经典”IFN通路，该通路可能参与了全新的生物学功能，如控制TGF信号传导成分的诱导。在第一个目标中，拟开展的实验将通过野生型（WT）小鼠的IFN和TGF¿In fb之间的串扰，研究Smad1/2/3的表达和磷酸化，IRF7和Smad7基因的表达，来研究控制促炎程序诱导和抑制生理平衡的机制。然后，我们将研究异常IFN信号的后果，促进IFN和TGF¿之间的新型串扰，并导致TLR激活的修饰平衡，促进IFNAR1-/-小鼠fb的纤维化表型。Aim 2将探讨IFN信号的损伤是否可能是SSc fb特征的促纤维化表型的基础，正如我们在IFNAR1 -/- fb中观察到的那样。本实验将测试IFN和polyIC对TGF -信号成分的影响，以及与正常fb相比，SSc中INF - / -信号的功能。最后，我们将检测选定的IFN和TGF介质IRF7和Smad7在SSc和对照皮肤中的体内表达。总之，这些结果将显著扩展我们对先天免疫激活、IFN和TGF在真皮纤维化中的作用的理解，并启发SSc发病机制的新观点，即IFN损伤可能是TGF激活失控的主要原因。此外，IFNAR2在控制TGF -信号激活方面的功能的新发现，为ifn介导的信号传导的复杂性增加了一种新的生物学反应，可能影响针对ifn的治疗方法的临床应用，不仅在SSc中，而且在其他疾病中。