Mechanisms of polarization of monocytes by DAMPs/PAMPs and C1q

DAMPs/PAMPs 和 C1q 的单核细胞极化机制

• 批准号: 10163790
• 负责人: Myoungsun Son
• 金额: $ 41.19万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163790
• 关键词: Actins; Anti-Inflammatory Agents; Atherosclerosis; Autoimmune Diseases; Binding; Cells; Collagen; Complement; Complement 1q; Cytoskeleton; Disease; Endothelium; Exposure to; Flare; Goals; HMGB1 gene; Homeostasis; Human; Immune; Immune system; Immunoglobulins; Inflammation; Inflammatory; Interferons; Intraperitoneal Injections; Investigation; Lead; Leukocytes; Leukotriene Production; Leukotrienes; Maintenance; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Obesity; Outcome; PTPN6 gene; Pathology; Pathway interactions; Pattern; Pattern recognition receptor; Peritonitis; Phosphorylation; Process; Production; Research; Resolution; Signal Pathway; Signal Transduction; Systemic Lupus Erythematosus; Tail; Testing; Therapeutic; Toll-like receptors; activation product; base; cell type; chronic inflammatory disease; complement 1q receptor; cytokine; immunoregulation; improved; inhibitor/antagonist; insight; lipid mediator; macrophage; monocyte; novel; pathogen; prevent; programs; receptor; receptor for advanced glycation endproducts; repaired; response

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.

项目总结/摘要 系统性红斑狼疮（SLE）是一种以高水平HMGB 1和低水平HMGB 2为特征的疾病。 C1q。损伤相关分子模式（DAMP）HMGB 1及其受体介导的HMGB 1的产生， 干扰素和促炎细胞因子并诱导M1样极化。补体成分C1 q 对单核细胞活化发挥抑制作用。单核细胞暴露于HMGB 1 + C1 q导致 M2类极化。这种单核细胞向抗炎性M2样程序的极化在以下情况下未观察到： 单核细胞单独暴露于C1 q。由于HMGB 1和C1 q都是进化上古老的分子， 高度保守，我们相信这可能是单核细胞分化和解决 炎症M1/ M2极化的不平衡是不适应的;在极端情况下，如上所述，它们 导致SLE，并在不太极端形式中导致“非消退性炎症”。我们建议进一步研究人类 探讨HMGB 1和HMGB 1 + C1 q对巨噬细胞极化的分子机制。 我们假设HMGB 1信号通过HMGB 1和HMGB 1加上C1 q共同连接HMGB 1和LAIR-1， 具有通过调节维持人和小鼠体内稳态的相关功能 细胞因子表达、脂质介质和microRNA。我们将首先测试Vav和SHP-1对 巨噬细胞介导的炎症和消退（目的1）。接下来，我们将确定HMGB 1和 HMGB 1加C1 q差异调节白三烯和专门的促消退介质的产生 （目标2）。最后，我们将描述HMGB 1和HMGB 1 + C1 q中上调或下调的microRNA 暴露的细胞我们将定义他们的耐受机制（目标3）。这些调查路线将提供 对M2样巨噬细胞极化的分子机制的新见解，2）为 免疫调节的研究，3）提高我们对SLE的理解和治疗选择， 炎症消退差的病症。