Interferon Regulation in Systemic Lupus

描述（由申请人提供）：I型干扰素（IFN），IFN α和IFN γ在系统性红斑狼疮（SLE）中高度表达，并与人SLE和小鼠模型的发病机制有关。I型干扰素作为SLE的致病因子和治疗靶点引起了人们极大的兴趣，尽管I型干扰素在SLE中也可能具有一些保护作用。迄今为止的证据表明，I型干扰素通过调节自身免疫和自身抗体的产生来影响SLE发病机制。关于I型干扰素对SLE的效应炎症期的影响，我们所知甚少，这是我们实验室感兴趣的一个领域。IFN生物学的一个关键方面是，先前暴露于I型IFN改变了随后的细胞对细胞外刺激的反应。我们假设巨噬细胞对细胞因子和炎症因子反应的改变代表了一种分子机制，通过这种机制，I型IFN促进炎症部位的巨噬细胞活化，从而促进SLE发病。为了验证这一假设，我们研究了I型干扰素对IL-10和免疫复合物的细胞应答的影响，这些因子在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，抑制巨噬细胞的功能，但矛盾的是，已牵连在SLE发病机制。我们发现用IFNa预处理改变了IL-10信号转导，增加了转录因子Stat 1（通常由IFNy激活）的IL-10激活，并导致IL-10激活“IFNy诱导基因”，包括趋化因子CXCL 9（Mig）和CXCL 10（IP-10）。我们假设IFN α对IL-10信号传导的“重编程”，使得IL-10激活趋化因子表达并随后将细胞募集到炎症部位，代表了IL-10促进SLE发病的一种机制。免疫复合物通过细胞表面Fc γ R的连接激活巨噬细胞效应子功能，包括细胞因子产生，并且在驱动SLE中的炎症中是重要的。IFNa改变了对免疫复合物的细胞应答，从而抑制了Fc γ R诱导的调节自身免疫和炎症的TNF α的产生。因此，我们认为，了解IFN调节Fc γ R功能和下游TNF α产生的机制对于了解IFN在SLE中的作用是重要的。在这个提议中，我们将研究IFN α诱导的IL-10和Fc γ R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，并确定新的治疗方法，以操纵SLE细胞因子活性的信号转导水平。

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.