Investigating monocyte activation pathways in lupus

研究狼疮中的单核细胞激活途径

• 批准号: 10731104
• 负责人: Insoo Kang
• 金额: $ 36.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-19 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731104
• 关键词: Address; Affect; Antibodies; Antigen-Antibody Complex; Autoantibodies; Autoantigens; Biological Assay; CASP1 gene; Caspase; Cell Death; Cell Death Induction; Cells; Characteristics; Clinical; Data; Dendritic Cells; Disease; Exposure to; Frequencies; Goals; Human; IL18 gene; Immune response; Inflammasome; Inflammation; Inflammatory; Interferon alpha; Interleukin-1 beta; Ku70 protein; Link; Lupus; Mediating; Membrane; Migration Inhibitory Factor; Molecular; Mus; Natural Immunity; Nuclear; Organ; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Pattern; Phosphotransferases; Production; Protein Kinase Interaction; Publishing; RIPK1 gene; RIPK3 gene; Reporting; Role; Serology; Small Nuclear Ribonucleoproteins; Systemic Lupus Erythematosus; TNF gene; Testing; Text; Treatment Efficacy; U1 Small Nuclear Ribonucleoprotein; adaptive immunity; anti-dsDNA antibodies; chemokine; cytokine; ds-DNA; high dimensionality; improved; inhibitor; lupus prone mice; mixed lineage kinase 3; monocyte; novel strategies; response; single cell analysis; single-cell RNA sequencing; synergism; tissue injury

Project Summary/Abstract: The pathologic hallmarks of systemic lupus erythematosus (SLE or lupus) are altered immune responses to nuclear autoantigens with autoantibody production and subsequent tissue injury. Studies have suggested a pathogenic role for innate immunity in lupus. Plasmacytoid dendritic cells and monocytes (MO) of innate immunity recognize ssRNA of the self antigen U1-small nuclear ribonucleoprotein (U1-snRNP) and dsDNA via TLRs 7/8 and 9, respectively, leading to the production of IFN-α, IL-1β and IL-18 which are linked to lupus pathogenesis and clinical manifestations. Regulated cell death can occur in distinct forms including pyroptosis and necroptosis. Pyroptosis and necroptosis cause inflammation by releasing inflammatory molecules such as cytokines, chemokines, and damage-associated molecular patterns (DAMPs). Pyroptosis is induced by the activation of the caspase-1-containing inflammasomes that cleave pro-IL-1β and - IL18 into IL-1β and IL-18, as well as gasdermin D (GASDMD) into the active form gasdermin D amino-terminal fragment (GASDMDN), the essential molecule for membrane pore formation in pyroptosis. Necroptosis that occurs independently of caspases is regulated by TNF-α, receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3), and downstream substrate pseudokinase mixed-lineage kinase domain-like (MLKL), the critical molecule for membrane disruption with the release of inflammatory molecules in necroptosis. RIPK3 and MLKL can also activate the NLRP3 inflammasome with IL-1β release, raising the possible interface of pyroptosis and necroptosis. Studies, including our own, support the implication of the inflammasome activation, pyroptosis, and necroptosis in lupus. We showed IL-1β and IL-18 production from human MO exposed to lupus U1-snRNP/anti- U1-snRNP antibody (Ab) or dsDNA/anti-dsDNA Ab immune complex (snRNP IC or dsDNA IC, also lupus IC refers to both) through the NLRP3 inflammasome activation which is enhanced by the cytokine macrophage migration inhibitory factor (MIF). However, there is a substantial scientific gap in our understanding of how pyroptic and necroptic pathways become activated, interface, and synergize to promote inflammation in lupus at molecular levels with contributing to unique clinical manifestations. Thus, we will test the hypotheses that lupus IC activate pyroptic and necroptic pathways in MO with synergistic interface in promoting inflammation and tissue injury and that the activation of such pathways alters in lupus contributing to clinicopathologic manifestations. The goal of the proposal is to address this hypothesis with: 1) Aim 1. Elucidate the mechanism and significance of the activation and interface of pyroptic and necroptic molecules in lupus; 2) Aim 2. Elucidate the “functional” alteration in monocytes that enhances pyroptosis- and necroptosis-mediated inflammation in lupus patients; and 3) Aim 3. Elucidate the role of macrophage migration inhibitory factor in promoting inflammation in lupus via regulating pyroptic and necroptic molecules. Our study would be highly informative in understanding lupus pathogenesis as well as in developing new approaches in evaluating and treating lupus patients.

项目摘要/摘要：系统性红斑狼疮的病理标志（SLE或狼疮）是 随后产生自身抗体和随后的组织损伤，对核自身抗原的免疫回应改变了。 研究表明，狼疮中先天免疫具有致病作用。浆细胞样树突状细胞和 自我抗原U1-Mall核核糖核蛋白的先天免疫识别的单核细胞（MO） （U1-SNRNP）和DSDNA分别通过TLR 7/8和9，导致IFN-α，IL-1β和IL-18的产生 与狼疮的发病机理和临床表现有关。受调节的细胞死亡可能发生在不同的 包括凋亡和坏死作用在内的形式。凋亡和坏死性通过释放引起创新 炎症分子，例如细胞因子，趋化因子和损伤相关的分子模式（湿）。 含caspase-1的炎症体的激活诱导了凋亡，这些炎症明确了pro-IL-1β和 - IL18进入IL-1β和IL-18，以及加油Min D（gasdmd）进入活性形式的gasdermin d氨基末端 片段（GASDMDN），膜孔形成的基本分子。坏死性 与病例独立于TNF-α，受体相互作用的蛋白激酶1和3（RIPK1）调节（RIPK1） 和RIPK3），以及下游底物假酶混合细胞酶域（MLKL），临界 RIPK3和MLKL 还可以通过释放IL-1β激活NLRP3炎性体，从而提高了凋亡的可能界面和 坏死性。包括我们自己在内的研究支持炎性体激活，凋亡和 狼疮中坏死性。我们显示了暴露于狼疮U1-SNRNP/抗狼疮的人Mo的IL-1β和IL-18产生 U1-SNRNP抗体（AB）或dsDNA/抗DSDNA AB Immunocomplex（SNRNP IC或DSDNA IC，也是狼疮IC 两者都通过NLRP3炎性体激活，这两者都通过细胞因子巨噬细胞增强 迁移抑制因子（MIF）。但是，我们对如何理解的科学差距很大 热带和坏死途径被激活，界面和协同作用，以促进狼疮的注射 分子水平有助于独特的临床表现。那就是我们将检验狼疮的假设 IC在MO中激活MO中的热带和坏死途径，并具有协同界面在促进注射和组织中 损伤和这种途径的激活在狼疮中改变了临床病理表现。 该提案的目的是通过以下方式解决这一假设：1）目标1。阐明机制和意义 狼疮中流向和坏死分子的激活和界面； 2）目标2。阐明“功能” 狼疮患者的单核细胞的改变，从而增强了凋亡和坏死介导的炎症；和 3）目标3。阐明巨噬细胞迁移抑制因子在促进狼疮中通过 调节流射和坏死分子。我们的研究将在理解狼疮方面有很高的信息 发病机理以及开发新方法评估和治疗狼疮患者。