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.

项目总结/文摘

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