Necroptosis signaling adaptors in inflammatory diseases
炎症性疾病中的坏死性凋亡信号适配器
基本信息
- 批准号:9247125
- 负责人:
- 金额:$ 41.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-01 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdjuvantAdoptive TransferAgonistAmyloidAnimalsApoptosisAreaBindingBiochemicalBiologicalBiologyBone MarrowCASP1 geneCASP8 geneCell DeathCell NucleusCell membraneCellsCessation of lifeChemicalsChronicColitisColon CarcinomaColorectal CancerComplementComplexCytokine GeneDefectDendritic CellsDiseaseEpithelial Cell ProliferationEpithelial CellsExperimental ModelsGene ActivationGene DeletionGene ExpressionGenetic RecombinationGenetic TranscriptionGoalsHematopoieticITGAX geneImmuneImmunityImmunobiologyImpairmentInflammationInflammatoryInflammatory disease of the intestineInjuryInterleukin-1Interleukin-1 betaIntestinesKnock-in MouseLamina PropriaLightLinkLipopolysaccharidesMalignant NeoplasmsMediatingMinorMolecularMusMutagenesisNuclearNuclear ExportNuclear TranslocationPathway interactionsPatternPharmacologyPhosphotransferasesPhysiologicalPlayPopulationPredispositionProtein IsoformsProtein KinaseRIPK1 geneReactive Oxygen SpeciesRecombinantsReporterReportingRoleRuptureSentinelSignal TransductionTLR3 geneTLR4 geneTNF geneTNFRSF5 geneTestingTherapeuticTissuesTranscriptional Activationautoinflammatorybasecell typechemokine receptorcytokineinhibitor-of-apoptosis proteininhibitor/antagonistinterleukin-22interleukin-23macrophagemutantnovelpreventprogramspublic health relevancereceptorreceptor functionresponsetissue repair
项目摘要
DESCRIPTION (provided by applicant): Inflammation is a key biological response with essential roles in protective immunity and auto- inflammatory diseases. Necroptosis is a non-apoptotic form of cell death with pro-inflammatory effects due to the release of cellular danger signals from ruptured plasma membranes. Receptor interacting protein kinase 3 (RIPK3) is an essential adaptor for necroptosis downstream of TNF-like death receptors and toll-like receptor 3 (TLR3) and TLR4. Ripk3-deficient mice are protected from many inflammatory diseases driven by inhibition of caspase 8 or the cellular inhibitor of apoptosis (IAP) proteins. These results led to the widely accepted view that RIPK3 drives inflammation through necroptosis. In contrast to these results, we found that Ripk3-deficient mice developed more severe chemical-induced colitis. The increased intestinal inflammation in Ripk3-deficient mice was not due to changes in cell death. Rather, Ripk3-deficient mice were impaired for expression of IL-1β, IL-23 and IL-22. Consistent with the known function of these cytokines in intestinal tissue repair, we found that injury-induced intestinal epithelial cell (IEC) proliferation was defective in Ripk3-deficient mice. These results indicate that immune sentinels in the intestinal lamina propria require RIPK3 to initiate a cytokine-driven tissue repair program. We found that in bone marrow derived dendritic cells (BMDCs), RIPK3 is required for IL-1β and IL-23 expression in response to stimulation with lipopolysaccharide (LPS), a TLR4 agonist. Similar to Ripk3-deficient mice treated with colitis-causing agent, reduced cytokine expression in Ripk3-deficient BMDCs was not due to reduced cell death. Rather, it was caused by defective activation of NF-B activation and impaired processing of pro-IL-1β. Specifically, RIPK3 is required for optimal activation of RelB-p50 heterodimer to promote IL-23 expression. In contrast, RIPK3 is not required for activation of RelA, c-Rel or p52. In addition, RIPK3 also promotes caspase 1 and caspase 8-mediated processing of pro-IL-1. These results indicate that RIPK3 critically controls RelB/p50-dependent IL-23 expression and pro-IL-1β processing and that these necroptosis-independent signaling functions are crucial for reparative inflammation. Based on these results, we propose two aims to investigate the molecular mechanisms by which RIPK3 regulates inflammatory cytokine expression in tissue repair responses. In Aim 1, we will study the biochemical mechanisms that controls RIPK3-mediated RelB-p50 nuclear translocation in BMDCs and CX3CR1+ macrophages from intestinal lamina propria. We hypothesize that RIPK3 and TRIF binding via the "RIP homotypic interaction motif" (RHIM) is critical for RelB-p50 activation and cytokine gene transcription. Moreover, we hypothesize that unlike necroptosis, this RHIM-mediated interaction does not involve amyloid conversion, RIPK1 or RIPK3 kinase activities. However, it is controlled by reactive oxygen species (ROS). We further hypothesize that upon activation by TRIF, RIPK3 functions as a chaperon to facilitate RelB-p50 nuclear translocation through direct binding to RelB. In addition to RelB-p50, we hypothesize that RIPK3 also promotes pro-IL-1 processing through an atypical RIPK1-RIPK3-FADD-caspase 8 complex. Moreover, cFLIP-long form binding to this complex critically promotes IL-1 secretion by preventing caspase 8-mediated apoptosis. In Aim 2, we will test the hypothesis that CX3CR1+ inflammatory macrophages in the intestinal lamina propria are the key immune effectors that produce IL-1 and IL-23 in a RIPK3-dependent manner. To test our hypothesis, we will use Cre-mediated recombination to generate mice with specific inactivation of RIPK3 in CD11c+ or CX3CR1+ cells. In addition, we will use mice expressing kinase inactive versions of RIPK1 and RIPK3 to determine the role of kinase activity in RIPK3-dependent cytokine expression and colitis induction. We will further test the hypothesis that correcting the early defect in cytokine expression and tissue repair can minimize chronic inflammation and susceptibility to inflammation-induced colon cancer. Successful completion of these studies will greatly enhance our understanding of the immunobiology of and relationship between RIPK3, dendritic cells/macrophages, necroptosis, tissue repair, inflammatory diseases and cancers.
描述(由申请人提供):炎症是一种关键的生物学反应,在保护性免疫和自身炎症性疾病中具有重要作用。坏死性凋亡是一种非凋亡形式的细胞死亡,由于细胞危险信号从破裂的质膜释放而具有促炎作用。受体相互作用蛋白激酶3(RIPK 3)是TNF样死亡受体和Toll样受体3(TLR 3)和TLR 4下游的坏死性凋亡的必需衔接子。Ripk 3缺陷型小鼠受到保护,免受许多炎症性疾病的影响,这些疾病是由半胱天冬酶8或细胞凋亡抑制剂(IAP)蛋白的抑制引起的。这些结果导致了广泛接受的观点,即RIPK 3通过坏死性凋亡驱动炎症。与这些结果相反,我们发现Ripk 3缺陷小鼠发生了更严重的化学诱导的结肠炎。Ripk 3缺陷小鼠的肠道炎症增加不是由于细胞死亡的变化。相反,Ripk 3缺陷小鼠的IL-1β、IL-23和IL-22表达受损。与这些细胞因子在肠组织修复中的已知功能一致,我们发现损伤诱导的肠上皮细胞(IEC)增殖在Ripk 3缺陷小鼠中是有缺陷的。这些结果表明,肠道固有层中的免疫哨兵需要RIPK 3启动一个由精氨酸驱动的组织修复程序。我们发现在骨髓来源的树突状细胞(BMDCs)中,RIPK 3是响应于脂多糖(LPS)(一种TLR 4激动剂)刺激而表达IL-1β和IL-23所必需的。与用结肠炎引起剂处理的Ripk 3缺陷小鼠相似,Ripk 3缺陷BMDC中细胞因子表达的减少不是由于细胞死亡减少。相反,它是由NF-κ B B活化缺陷和pro-IL-1β加工受损引起的。具体而言,RIPK 3是RelB-p50异源二聚体最佳活化以促进IL-23表达所需的。相反,RIPK 3对于RelA、c-Rel或p52的激活不是必需的。此外,RIPK 3还促进胱天蛋白酶1和胱天蛋白酶8介导的pro-IL-1 β加工。这些结果表明,RIPK 3严格控制RelB/p50依赖性IL-23表达和pro-IL-1β加工,并且这些坏死凋亡非依赖性信号传导功能对于修复性炎症至关重要。 基于这些结果,我们提出了两个目标,以研究RIPK 3调节组织修复反应中炎性细胞因子表达的分子机制。在目的1中,我们将研究控制RIPK 3介导的RelB-p50在BMDCs和CX 3CR 1+巨噬细胞中的核转位的生化机制。我们假设RIPK 3和TRIF通过“RIP同型相互作用基序”(RHIM)结合对于RelB-p50激活和细胞因子基因转录至关重要。此外,我们假设与坏死性凋亡不同,这种RHIM介导的相互作用不涉及淀粉样蛋白转化、RIPK 1或RIPK 3激酶活性。然而,它是由活性氧(ROS)控制的。我们进一步假设,在TRIF激活后,RIPK 3作为伴侣分子通过直接结合RelB促进RelB-p50核转位。除了RelB-p50,我们假设RIPK 3也通过非典型的RIPK 1-RIPK 3-FADD-半胱天冬酶8复合物促进pro-IL-1 β加工。此外,cFLIP-长形式与该复合物的结合通过阻止胱天蛋白酶8介导的细胞凋亡而显著促进IL-1 β分泌。在目标2中,我们将检验以下假设:肠固有层中的CX 3CR 1+炎性巨噬细胞是以RIPK 3依赖性方式产生IL-1 β和IL-23的关键免疫效应物。为了验证我们的假设,我们将使用Cre介导的重组来产生在CD 11 c+或CX 3CR 1+细胞中具有RIPK 3特异性失活的小鼠。此外,我们将使用表达RIPK 1和RIPK 3的激酶失活版本的小鼠来确定激酶活性在RIPK 3依赖性细胞因子表达和结肠炎诱导中的作用。我们将进一步检验这一假设,即纠正细胞因子表达和组织修复的早期缺陷可以最大限度地减少慢性炎症和对炎症诱导的结肠癌的易感性。这些研究的成功完成将极大地增强我们对RIPK 3、树突状细胞/巨噬细胞、坏死性凋亡、组织修复、炎性疾病和癌症的免疫生物学和关系的理解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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FRANCIS Kaming CHAN其他文献
FRANCIS Kaming CHAN的其他文献
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{{ truncateString('FRANCIS Kaming CHAN', 18)}}的其他基金
2020 Cell Death Gordon Research Conference & Gordon Research Seminar
2020细胞死亡戈登研究会议
- 批准号:
9890344 - 财政年份:2021
- 资助金额:
$ 41.88万 - 项目类别:
Viral inhibition of cell death in host immune responses
病毒抑制宿主免疫反应中的细胞死亡
- 批准号:
10199958 - 财政年份:2020
- 资助金额:
$ 41.88万 - 项目类别:
Necroptosis signaling adaptors in inflammatory diseases
炎症性疾病中的坏死性凋亡信号适配器
- 批准号:
9106004 - 财政年份:2016
- 资助金额:
$ 41.88万 - 项目类别:
Regulation of necrotic cell death by protein kinase A and cylindromatosis
蛋白激酶 A 和圆柱瘤病对坏死细胞死亡的调节
- 批准号:
7875932 - 财政年份:2010
- 资助金额:
$ 41.88万 - 项目类别:
Regulation of necrotic cell death by protein kinase A and cylindromatosis
蛋白激酶 A 和圆柱瘤病对坏死细胞死亡的调节
- 批准号:
8034218 - 财政年份:2010
- 资助金额:
$ 41.88万 - 项目类别:
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