Pericyte-Macrophage Interactions Maintain CNS Immune Tolerance
周细胞-巨噬细胞相互作用维持中枢神经系统免疫耐受
基本信息
- 批准号:10279865
- 负责人:
- 金额:$ 39.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-15 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:Antigen PresentationAntigen-Presenting CellsAntigensAreaAutoimmune DiseasesBiological AssayBloodBlood - brain barrier anatomyBlood flowBrainBrain InjuriesCNS autoimmune diseaseCRISPR/Cas technologyCellsCommunicationCytoplasmic OrganelleDataDemyelinationsEnvironmentEventExperimental Autoimmune EncephalomyelitisFamilyGenesGeneticGenetic PolymorphismGlycine decarboxylaseImmuneImmune ToleranceInfiltrationInflammationLDL-Receptor Related Protein 1LeadLesionLipoprotein ReceptorMediatingMembraneMeningealMeningesMessenger RNAModelingMultiple SclerosisMusMyelinNatureNerve DegenerationNeuraxisNeurologic SymptomsPericytesPeripheralPhenotypeProcessProteinsRNARNA ProcessingRoleSignal TransductionSiteSpinal CordSurfaceT cell responseT-Cell ActivationT-LymphocyteTestingTissuesangiogenesisantigen-specific T cellsautoreactive T cellcell typegenome wide association studyhealingimmunosuppressedin vivomacrophagemesenchymal stromal cellmigrationmultiple sclerosis patientneuroinflammationneurovascular unitnew therapeutic targetnovelnovel therapeuticsprogramsscavenger receptortraffickinguptake
项目摘要
Pericyte-Macrophage Interactions Maintain CNS Immune Tolerance
ABSTRACT
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) where infiltrating T cells
ultimately lead to the destruction of myelin. T cells initially accumulate in the perivascular space of the brain and
the meninges where they must interact with antigen presenting cells prior to activating and infiltrating into the
parenchyma. This suggests immune interactions in the perivascular space may serve as a checkpoint and
determine the fate of infiltrating T cells. Macrophages and pericytes are two important cells in the perivascular
space of the brain and meninges. Under homeostatic conditions, border macrophages have an immuno-
surveillant phenotype and express surface markers typical for macrophages that help with healing tissues. The
signals that maintain CNS border macrophages in this state are unknown. Pericytes also reside in the
perivascular space and are a key component of the neurovascular unit where they regulate blood flow,
angiogenesis, the blood-brain barrier (BBB), and neuroinflammation. Although each cell type has be implicated
in multiple sclerosis (MS), the communication between the 2 cell types has not been described. Our preliminary
data demonstrate that cultured pericytes suppress the activation of T cells through engaging macrophages.
Pericytes directly contact macrophages and reprogram them to downregulate genes need for antigen
presentation and T cells activation. Pericytes/macrophage interactions are mediated by lipoprotein receptor-
related proteins (LRP) on macrophages and dependent on p-bodies in pericytes. P-bodies are membrane-less,
cytoplasmic organelles that contain mRNAs enriched in regulatory functions. In vivo, pericytes reside in close
proximity to perivascular and meningeal macrophages and have the potential to interact closely with
macrophages. When we deleted pericytes in vivo, CNS antigen specific T cells infiltrate the perivascular space
of the meninges in a manner that was dependent on macrophages. T cells further infiltrate into the parenchyma
when triggered by a second signal from the parenchymal.
We hypothesize that under homeostatic conditions pericytes communicate with perivascular and meningeal
macrophages to maintain them in an immunosuppressive and surveillant state. This contributes to the immuno-
privileged nature of the brain. In MS, we hypothesize that communication between pericytes and macrophages
breakdown and this unleashes CNS macrophages into a proinflammatory state that contributes to T cell
activation and infiltration into the brain. In this proposal, we will determine if pericytes instruct perivascular
macrophages to inhibit brain-specific T cells from entering the parenchyma, investigate whether pericytes
reprogram CNS macrophages in vivo, and determine if macrophages must engulf components of pericytes in
order to be reprogramed to suppress T cells. Overall, this proposal will investigate an unexplored interaction
between pericytes and CNS border macrophages.
周细胞-巨噬细胞相互作用维持中枢神经系统免疫耐受
项目成果
期刊论文数量(0)
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Anthony J Filiano其他文献
Breaking bad blood: β2-microglobulin as a pro-aging factor in blood
打破不良血液:β2-微球蛋白作为血液中的促衰老因子
- DOI:
10.1038/nm.3926 - 发表时间:
2015-08-06 - 期刊:
- 影响因子:50.000
- 作者:
Anthony J Filiano;Jonathan Kipnis - 通讯作者:
Jonathan Kipnis
Anthony J Filiano的其他文献
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{{ truncateString('Anthony J Filiano', 18)}}的其他基金
Pericyte-Macrophage Interactions Maintain CNS Immune Tolerance
周细胞-巨噬细胞相互作用维持中枢神经系统免疫耐受
- 批准号:
10628006 - 财政年份:2021
- 资助金额:
$ 39.52万 - 项目类别:
Pericyte-Macrophage Interactions Maintain CNS Immune Tolerance
周细胞-巨噬细胞相互作用维持中枢神经系统免疫耐受
- 批准号:
10445061 - 财政年份:2021
- 资助金额:
$ 39.52万 - 项目类别:
Transglutaminase 2 decreases ischemic insult by attenuating hypoxic signaling.
转谷氨酰胺酶 2 通过减弱缺氧信号来减少缺血性损伤。
- 批准号:
7609278 - 财政年份:2009
- 资助金额:
$ 39.52万 - 项目类别:
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