Interferon Regulation in Systemic Lupus

I型干扰素(IFN)，IFNA和IFNp，在系统性红斑狼疮(SLE)中高表达，并有 与人类系统性红斑狼疮和小鼠模型的致病因素有关。人们对第一类IFNsas非常感兴趣 系统性红斑狼疮的致病因素和治疗靶点，尽管I型干扰素对系统性红斑狼疮也有一定的保护作用。 到目前为止的证据表明，I型干扰素通过调节SLE的发展而影响SLE的发病。 自身免疫和自身抗体的产生：对I型干扰素对效应器炎症的影响知之甚少 SLE的阶段，这是我们实验室感兴趣的一个领域。 干扰素生物学的一个关键方面是，以前接触I型IFN会改变随后的细胞反应 细胞外刺激。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I型干扰素促进炎症部位巨噬细胞活化的分子机制，以及 从而参与了SLE的发病机制。为了验证这一假设，我们研究了I型干扰素对细胞的影响。 对IL-10和免疫复合体的反应，这些因子在系统性红斑狼疮中高度表达，并与 发病机制。IL-10是一种主要的免疫抑制和抗炎细胞因子，可抑制巨噬细胞 功能，但矛盾的是，已经牵涉到SLE的发病机制。我们发现IFNA的预处理改变了 IL-10信号转导，增加IL-10对转录因子STAT1的激活(通常由IFNy激活)和 导致IL-10被“IFNy诱导基因”激活，包括趋化因子CXCL9(Mig)和CXCL10(IP-10)。 我们假设，IFNA对IL-10信号进行了重新编程，使IL-10激活趋化因子的表达和 随后细胞重新聚集到炎症部位，是IL-10促进SLE的一种机制 发病机制。免疫复合物通过连接巨噬细胞激活巨噬细胞效应器功能，包括细胞因子的产生 细胞表面的FCyRs，在SLE的炎症反应中起重要作用。IFNA改变细胞对免疫的反应 复合体，使FcyR诱导的TNFa的产生，调节自身免疫和炎症，是 被压制了。因此，我们建议理解IFN调节FcyR功能及其下游的机制 TNFa的产生对于了解干扰素在系统性红斑狼疮中的作用很重要。在这项建议中，我们将调查 IFNA诱导IL-10和FcyR作用改变的分子机制及(病理)生理意义 这些实验将深入了解系统性红斑狼疮的分子发病机制，并找到新的治疗方法。 在信号转导水平上调控SLE的细胞因子活性。

The type I interferons (IFNs), IFNa and IFNp, are highly expressed in systemic lupus erythematosus(SLE) and have been implicated in the pathogene;sisof human SLE and in murine models. There is great interest in type I IFNsas pathogenic factors and therapeutic targets in SLE, although type I IFNs may also have some protective effects inSLE. Evidence to date indicates that type I IFNs impact upon SLE pathogenesis by regulating the developmentof 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 pretreatmentwith IFNa altered IL-10 signal transduction, increasing IL-10 activation of the transcription factor Statl (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 expressionand 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 understandingmechanisms by which IFNs regulate FcyR function anddownstream 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 manipulatecytokine activity in SLE at the level of signal transduction.