Mechanisms of polarization of monocytes by DAMPs/PAMPs and C1q

DAMPs/PAMPs 和 C1q 的单核细胞极化机制

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要全身性红斑狼疮（SLE）是一种疾病，其特征是高水平的HMGB1和低水平 C1Q。损伤相关的分子模式（潮湿）HMGB1及其接收器的愤怒触发产生干扰素和促炎细胞因子并诱导M1样极化。补体组件C1Q 单核细胞暴露于HMGB1加上C1Q导致 M2样偏振。单核细胞的极化与抗炎M2样程序没有看到单核细胞仅暴露于C1Q。由于HMGB1和C1Q都是进化的旧分子，并且是高度保守，我们认为这可能是单核细胞分化和分辨率的重要范式炎。 M1/M2极化的失衡是适应不良的；在极端，如上所述，他们导致SLE并以极端形式导致“非解决创新”。我们建议对人类的进一步研究单核细胞探索HMGB1和HMGB1 Plus C1Q的巨噬细胞极化的分子机制。我们假设HMGB1通过RAGE和HMGB1加C1Q共同绑扎愤怒和Lair-1信号传导通过调节，具有与人类和小鼠维持体内平衡有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对巨噬细胞介导的注射和分辨率（AIM 1）。接下来，我们将确定HMGB1和 HMGB1加上C1Q差异调节白细胞的产生和专业的支持介质的介体（SPM）（目标2）。最后，我们将在HMGB1和HMGB1加C1Q中向上或下调的microRNA划定暴露的细胞。我们将定义它们的容忍机制（AIM 3）。这些投资线将1）提供对M2样巨噬细胞极化的分子机制的新见解，2）为新模型贡献免疫调节的研究以及3）提高我们的理解以及对SLE的热选择，以及炎症分辨率较差的情况。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
通讯作者：
Son M

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

Editorial: The Role of HMGB1 in Immunity.

DOI：
10.3389/fimmu.2020.594253
发表时间：
2020
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Son M;Diamond B;Shin JS
通讯作者：
Shin JS

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.)
影响因子：
0
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