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CNS免疫耐受
摘要
多发性硬化症(MS)是一种中枢神经系统(CNS)的自身免疫性疾病,其中浸润的T细胞
最终导致髓磷脂的破坏。T细胞最初积聚在脑的血管周围空间中,
在脑膜中,它们必须在活化和浸润到脑膜中之前与抗原呈递细胞相互作用。
薄壁组织这表明血管周围空间中的免疫相互作用可以作为检查点,
决定浸润性T细胞的命运巨噬细胞和周细胞是血管周围的两种重要细胞
大脑和脑膜的空间。在稳态条件下,边缘巨噬细胞具有免疫-
监视表型并表达巨噬细胞典型表面标志物,其有助于愈合组织。的
维持CNS边缘巨噬细胞处于这种状态的信号是未知的。周细胞也存在于
血管周围空间并且是神经血管单元的关键组成部分,在那里它们调节血流,
血管生成、血脑屏障(BBB)和神经炎症。尽管每种细胞类型都与
在多发性硬化症(MS)中,2种细胞类型之间的通讯尚未被描述。我们的初步
数据表明培养的周细胞通过接合巨噬细胞抑制T细胞的活化。
周细胞直接接触巨噬细胞并重新编程它们以下调抗原所需的基因
呈递和T细胞活化。周细胞/巨噬细胞相互作用由脂蛋白受体介导-
相关蛋白(LRP)和依赖于周细胞中的P体。P体无膜,
含有富含调节功能的mRNA的细胞质细胞器。在体内,周细胞位于
接近血管周围和脑膜巨噬细胞,并有可能与
巨噬细胞当我们在体内去除周细胞时,CNS抗原特异性T细胞浸润血管周围空间
以一种依赖于巨噬细胞的方式。T细胞进一步向实质浸润
当被来自脑实质的第二信号触发时。
我们假设在稳态条件下,周细胞与血管周围和脑膜沟通,
巨噬细胞以维持它们处于免疫抑制和监视状态。这有助于免疫-
大脑的特权在多发性硬化症中,我们假设周细胞和巨噬细胞之间的通讯
这释放中枢神经系统巨噬细胞进入促炎状态,有助于T细胞
激活并渗入大脑在这个建议中,我们将确定周细胞是否指导血管周围
巨噬细胞抑制脑特异性T细胞进入实质,研究周细胞是否
在体内重新编程CNS巨噬细胞,并确定巨噬细胞是否必须吞噬周细胞的成分,
重新编程以抑制T细胞。总体而言,该提案将调查一种未探索的相互作用
周细胞和中枢神经系统边缘巨噬细胞之间。
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)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Tri-Signal Artificial Antigen Presenting Cells for Cancer Immunotherapy
用于癌症免疫治疗的三信号人工抗原呈递细胞
- 批准号:
10751133 - 财政年份:2023
- 资助金额:
$ 39.52万 - 项目类别:
Microfluidic Precision Engineered Artificial Antigen Presenting Cells for Cancer Immunotherapy
用于癌症免疫治疗的微流控精密工程人工抗原呈递细胞
- 批准号:
10696138 - 财政年份:2022
- 资助金额:
$ 39.52万 - 项目类别:
The role of microglia as antigen presenting cells in Globoid Cell Leukodystrophy
小胶质细胞作为抗原呈递细胞在球状细胞脑白质营养不良中的作用
- 批准号:
10663066 - 财政年份:2022
- 资助金额:
$ 39.52万 - 项目类别:
The role of microglia as antigen presenting cells in Globoid Cell Leukodystrophy
小胶质细胞作为抗原呈递细胞在球状细胞脑白质营养不良中的作用
- 批准号:
10537159 - 财政年份:2022
- 资助金额:
$ 39.52万 - 项目类别:
Analysis of the function of antigen-presenting cells present in the stroma of colorectal cancer and the intracellular microbiome
结直肠癌基质中抗原呈递细胞和细胞内微生物组的功能分析
- 批准号:
21K08723 - 财政年份:2021
- 资助金额:
$ 39.52万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Class II artificial antigen presenting cells for cancer immunotherapy
用于癌症免疫治疗的 II 类人工抗原呈递细胞
- 批准号:
10156950 - 财政年份:2021
- 资助金额:
$ 39.52万 - 项目类别:
The role of CX3CR1+ antigen presenting cells in T cell selection and central tolerance"
CX3CR1抗原呈递细胞在T细胞选择和中枢耐受中的作用"
- 批准号:
10631854 - 财政年份:2021
- 资助金额:
$ 39.52万 - 项目类别:
Reprogramming Cancer Cells into Antigen Presenting Cells: Cancer Vaccination with mRNA Enabled by Charge-Altering Releasable Transporters
将癌细胞重编程为抗原呈递细胞:通过改变电荷的可释放转运蛋白实现 mRNA 的癌症疫苗接种
- 批准号:
10153927 - 财政年份:2021
- 资助金额:
$ 39.52万 - 项目类别:
Class II artificial antigen presenting cells for cancer immunotherapy
用于癌症免疫治疗的 II 类人工抗原呈递细胞
- 批准号:
10331830 - 财政年份:2021
- 资助金额:
$ 39.52万 - 项目类别:
Analysis on detrimental interplay between pathogenic helper T cells, inflammatory antigen-presenting cells and disease-associated microglia in chronic pathogenesis of multiple sclerosis
多发性硬化症慢性发病机制中致病性辅助 T 细胞、炎症抗原呈递细胞和疾病相关小胶质细胞之间的有害相互作用分析
- 批准号:
20K16294 - 财政年份:2020
- 资助金额:
$ 39.52万 - 项目类别:
Grant-in-Aid for Early-Career Scientists