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: 10408116
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408116
• 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; 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.

项目概要/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 M1 样极化。补体成分 C1q 对单核细胞活化发挥抑制作用。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不会出现： 单核细胞单独暴露于 C1q。由于 HMGB1 和 C1q 都是进化上古老的分子，并且 高度保守，我们相信这可能是单核细胞分化和解决的重要范例 炎。 M1/M2 极化的不平衡是适应不良的；在极端情况下，如上所述，他们 导致系统性红斑狼疮，并在不太极端的情况下导致“无法解决的炎症”。我们建议在人类中进行进一步的研究 单核细胞探索 HMGB1 和 HMGB1 加 C1q 巨噬细胞极化的分子机制。 我们假设 HMGB1 信号通过 RAGE 和 HMGB1 加上 C1q 共同连接 RAGE 和 LAIR-1 通过调节具有与维持人类和小鼠体内平衡相关的功能 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（目标 1）。接下来，我们将确定 HMGB1 和 HMGB1 加 C1q 差异调节白三烯和专门的促分解介质的产生 （SPM）（目标 2）。最后，我们将描述 HMGB1 和 HMGB1 加 C1q 中上调或下调的 microRNA 暴露的细胞。我们将定义他们的容忍机制（目标 3）。这些调查路线将 1) 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，以及 炎症消退不佳的情况。

项目成果

The Immune Tolerance Role of the HMGB1-RAGE Axis.

• DOI: 10.3390/cells10030564
• 发表时间: 2021-03-05
• 期刊: Cells
• 影响因子: 6
• 作者: Watanabe H;Son M
• 通讯作者: Son M

Understanding the contextual functions of C1q and LAIR-1 and their applications.

• DOI: 10.1038/s12276-022-00774-4
• 发表时间: 2022-05
• 期刊: Experimental & molecular medicine
• 影响因子: 12.8
• 作者: Son M

The collagen structure of C1q induces wound healing by engaging discoidin domain receptor 2.

• DOI: 10.1186/s10020-021-00388-y
• 发表时间: 2021-10-03
• 期刊: Molecular medicine (Cambridge, Mass.)
• 作者: Hayuningtyas RA;Han M;Choi S;Kwak MS;Park IH;Lee JH;Choi JE;Kim DK;Son M;Shin JS
• 通讯作者: Shin JS

HIF-1α is a negative regulator of interferon regulatory factors: Implications for interferon production by hypoxic monocytes.

• DOI: 10.1073/pnas.2106017118
• 发表时间: 2021-06-29
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Peng T;Du SY;Son M;Diamond B
• 通讯作者: Diamond B