Mechanisms of polarization of monocytes by DAMPs/PAMPs and C1q

项目摘要/摘要 系统性红斑狼疮(SLE)是一种以高水平HMGB1和低水平HMGB1为特征的疾病 C1q.损伤相关分子模式(DAMP)HMGB1及其受体RAGE触发 干扰素和促炎细胞因子，并诱导类M1极化。补体成分C1q 对单核细胞的激活有抑制作用。单核细胞暴露于HMGB1加C1q会导致 类M2偏振。单核细胞向抗炎M2样程序的这种极化在以下情况下看不到 单核细胞仅暴露于C1q。因为HMGB1和C1q都是进化上较老的分子 高度保守，我们认为这可能是单核细胞分化和解决的一个重要范例 发炎。M1/M2两极分化的失衡是不适应的；如上所述，在极端情况下，它们 导致系统性红斑狼疮，在不太极端的情况下会导致“未消退的炎症”。我们建议对人类进行进一步的研究 目的：探讨HMGB1及HMGB1+C1q对巨噬细胞极化的分子机制。 我们推测HMGB1信号通过RAGE和HMGB1+C1q共同连接RAGE和LAIR-1 通过调节与维持人体和小鼠的动态平衡有关的功能 细胞因子表达、脂质介质和microRNAs。我们将首先测试Vav和SHP-1对 巨噬细胞介导的炎症和消解(目标1)。接下来，我们将确定HMGB1和 HMGB1加C1q差异性调节白三烯和专业促分解介质的产生 (SPMS)(目标2)。最后，我们将描述HMGB1和HMGB1+C1q中上调或下调的microRNAs 暴露的细胞。我们将定义他们的容忍机制(目标3)。这些调查线将提供1) 对类M2巨噬细胞极化的分子机制的新见解，2)贡献了新的模型 免疫调节的研究，以及3)提高我们对SLE的理解和治疗选择，以及 炎症消退差的情况。

PROJECT SUMMARY/ABSTRACT Systemic Lupus Erythematosus (SLE) is a disease characterized by high levels of HMGB1 and low levels of C1q. The damage-associated molecular pattern (DAMP) HMGB1 and its receptor RAGE trigger production of interferon and pro-inflammatory cytokines and induce an M1-like polarization. Complement component C1q exerts a suppressive effect on monocyte activation. Exposure of monocytes to HMGB1 plus C1q leads to an M2-like polarization. This polarization of monocytes to an anti-inflammatory M2-like program is not seen when monocytes are exposed to C1q alone. As both HMGB1 and C1q are evolutionarily old molecules and are highly conserved, we believe this is likely an important paradigm for monocyte differentiation and resolution of inflammation. Imbalances in M1/ M2 polarization are maladaptive; in the extreme, as mentioned above, they lead to SLE and in less extreme forms to “non-resolving inflammation”. We propose further studies in human monocytes to explore the molecular mechanism of macrophage polarization by HMGB1 and HMGB1 plus C1q. We hypothesize that HMGB1 signaling through RAGE and HMGB1 plus C1q co-ligating RAGE and LAIR-1 have functions relevant to the maintenance of homeostasis both in humans and mice through regulating cytokine expression, lipid mediators and microRNAs. We will first test the contribution of Vav and SHP-1 to macrophage mediated inflammation and resolution (Aim 1). Next, we will determine whether HMGB1 and HMGB1 plus C1q differentially regulate production of leukotrienes and specialized pro-resolving mediators (SPMs) (Aim 2). Finally, we will delineate up-or down-regulated microRNAs in HMGB1 and HMGB1 plus C1q exposed cells. We will define their tolerance mechanisms (Aim 3). These lines of investigation will 1) offer novel insights into the molecular mechanism of M2-like macrophage polarization, 2) contribute new models to the study of immune regulation, and 3) improve our understanding, and therapeutic options for SLE, and conditions with poor resolution of inflammation.