Interferon Regulation in Systemic Lupus

描述(申请人提供)：I型干扰素(IFN)，IFNA和干扰素，在系统性红斑狼疮(SLE)中高度表达，并与人类SLE的发病机制和小鼠模型有关。I型IFN作为SLE的致病因子和治疗靶点备受关注，尽管I型IFN在SLE中也可能具有一定的保护作用。到目前为止的证据表明，I型IFN通过调节自身免疫和自身抗体的产生而影响SLE的发病。关于I型干扰素对系统性红斑狼疮效应器炎症阶段的影响，人们知之甚少，这是我们实验室感兴趣的领域。干扰素生物学的一个关键方面是，先前暴露于I型IFN会改变随后的细胞对细胞外刺激的反应。我们推测，巨噬细胞对细胞因子和炎症因子反应的改变代表了I型干扰素促进炎症部位巨噬细胞活化的分子机制，从而促进了SLE的发病。为了验证这一假设，我们研究了I型IFN对细胞对IL-10和免疫复合体的反应的影响，这些因素在SLE中高度表达，并与发病机制有关。IL-10是一种主要的免疫抑制和抗炎细胞因子，可以抑制巨噬细胞的功能，但矛盾的是，它与SLE的发病机制有关。我们发现，IFNA预处理改变了IL-10的信号转导，增加了转录因子STAT1(通常由IFNy激活)的IL-10激活，并导致了包括趋化因子CXCL9(Mig)和CXCL10(IP-10)在内的“IFNy诱导基因”的IL-10激活。我们假设，IFNA对IL-10信号的重新编程，使得IL-10激活趋化因子的表达，并随后将细胞募集到炎症部位，是IL-10参与SLE发病的一种机制。免疫复合体通过连接细胞表面FcyRs激活巨噬细胞效应器功能，包括细胞因子的产生，在SLE的炎症反应中起重要作用。IFNA改变了细胞对免疫复合体的反应，从而抑制了FcyR诱导的TNFa的产生，而TNFa既调节自身免疫又调节炎症。因此，我们认为，了解IFN调节FcyR功能和下游TNFa产生的机制对于理解IFN在SLE中的作用是重要的。在这项建议中，我们将探讨IFNA诱导IL-10和FcyR作用改变的分子机制和(病理)生理学意义。这些实验将深入了解SLE的分子发病机制，并找到在信号转导水平上操纵SLE细胞因子活性的新的治疗方法。

DESCRIPTION (provided by applicant): The type I interferons (IFNs), IFNa and IFN¿, are highly expressed in systemic lupus erythematosus (SLE) and have been implicated in the pathogenesis of human SLE and in murine models. There is great interest in type I IFNs as pathogenic factors and therapeutic targets in SLE, although type I IFNs may also have some protective effects in SLE. Evidence to date indicates that type I IFNs impact upon SLE pathogenesis by regulating the development of autoimmunity and autoantibody production. Less is known about the effects of type I IFNs on the effector inflammatory phase of SLE, which is an area of interest of our lab. A key aspect of IFN biology is that previous exposure to type I IFNs alters subsequent cellular responses to extracellular stimuli. We hypothesized that alteration of macrophage responses to cytokines and inflammatory factors represents a molecular mechanism by which type I IFNs promote macrophage activation at sites of inflammation, and thereby contribute to SLE pathogenesis. To test this hypothesis, we examined the effects of type I IFNs on cellular responses to IL-10 and immune complexes, factors that are highly expressed in SLE and have been implicated in pathogenesis. IL-10 is a predominantly immunosuppressive and anti-inflammatory cytokine that inhibits macrophage function, but, paradoxically, has been implicated in SLE pathogenesis. We found that pretreatment with IFNa altered IL-10 signal transduction, increasing IL-10 activation of the transcription factor Stat1 (typically activated by IFNy) and resulting in IL-10 activation of "IFNy-inducible genes", including the chemokines CXCL9 (Mig) and CXCL10 (IP-10). We hypothesize that IFNa "reprogramming" of IL-10 signaling, such that IL-10 activates chemokine expression and subsequent recruitment of cells to inflammatory sites, represents one mechanism by which IL-10 contributes to SLE pathogenesis. Immune complexes activate macrophage effector functions, including cytokine production, by ligation of cell surface FcyRs and are important in driving inflammation in SLE. IFNa altered cellular responses to immune complexes, such that FcyR-induced production of TNFa, which regulates both autoimmunity and inflammation, was suppressed. Thus, we propose that understanding mechanisms by which IFNs regulate FcyR function and downstream TNFa production is important for understanding the role of IFNs in SLE. In this proposal, we will investigate the molecular mechanisms and (patho) physiological significance of IFNa-induced alterations in IL-10 and FcyR action. These experiments will yield insight into the molecular pathogenesis of SLE and identify novel therapeutic approaches to manipulate cytokine activity in SLE at the level of signal transduction.