Role of group 2 innate lymphoid cells in myocardial infarction
第 2 组先天淋巴细胞在心肌梗死中的作用
基本信息
- 批准号:10365354
- 负责人:
- 金额:$ 68.21万
- 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:2021-12-15 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:Acute myocardial infarctionAdipocytesAdipose tissueAdoptive TransferAllergicApoptosisBasic ScienceBloodBlood CirculationBone MarrowBone Marrow TransplantationCardiacCardiac MyocytesCationsCause of DeathCell DeathCell physiologyCellsClinical ResearchCoronary heart diseaseDendritic CellsDevelopmentDiphtheria ToxinEosinophil cationic proteinEventFemaleFibroblastsFibrosisGranulocyte-Macrophage Colony-Stimulating FactorHeartHeart BlockHeart InjuriesHeart failureHumanIL2 geneIL3 GeneIL4 geneIL5 geneImmuneIn VitroInflammationInterleukin-10Interleukin-13LipidsLymphocyteLymphoid CellMediatingMediator of activation proteinMolecularMusMyocardialMyocardial InfarctionMyocardial dysfunctionObesityOrthologous GeneParasitic infectionPatientsPlayPrevalenceProtein BiosynthesisProteinsRecombinantsRegulatory T-LymphocyteReportingResidual stateRiskRisk FactorsRoleSex DifferencesShort Interspersed Nucleotide ElementsSiteTestingWild Type Mousealpha Toxinarginaseatherogenesisbasecardiac repaircardioprotectionconditional knockoutcoronary fibrosiscytokineeosinophilheart functionimprovedischemic injurymalemigrationmortalityobesity developmentprogrammed cell death protein 1protein expressionrecruitresponsesuccess
项目摘要
Coronary heart disease remains the leading cause of deaths in the US. Despite the success of lipid lowering,
residual risk remains. Recent clinical studies support the role of inflammation in CVD, a longstanding topic of
basic research. Group 2 innate lymphoid cells (ILC2) are innate lymphocytes that play essential role in obesity
by promoting adipocyte beiging and recruiting beige cells to the white adipose tissue, thereby limiting obesity
development. Limited information is available regarding ILC2 function in CVD, although transplantation of
bone-marrow from ILC2-deficient mice promoted atherogenesis. Eosinophils (EOS) accumulate in blood or at
the site of inflammation after allergic sensitization or parasite infection. Blood EOS count and EOS cationic
protein (ECP) levels associate positively with major CV risk factors and CVD prevalence and mortality. Yet
other studies reported reduced blood EOS count and ECP levels in patients with major adverse cardiac events
and heart failure. Therefore, the role of ILC2 and EOS in human CVD remains unsettled. Our preliminary
studies demonstrated ILC2 accumulation in mouse heart after myocardial infarction (MI). ILC2 deficiency
(ILC2KO) or diphtheria toxin A (DTA)-induced ILC2 depletion (ILC2DTA) exacerbated cardiac dysfunction,
myocardial cell death and fibrosis post-MI. Further study showed that ILC2 deficiency blunted blood IL5, an
essential type-2 cytokine from ILC2 that controls the expansion and migration of EOS, dendritic cells (DC), and
regulatory T cells (Treg) to the bloodstream or the site of inflammation. FACS analysis revealed deficiency of
splenic, blood, or heart EOS and DC in ILC2KO mice post-MI. Administration of mouse recombinant IL5
reversed EOS loss in blood, providing a mechanistic explanation of ILC2 activity in alleviating cardiac
dysfunction post-MI and suggesting a concurrent cardioprotective role of EOS and ILC2 in post-MI heart.
Consistent with this hypothesis, exacerbated post-MI cardiac dysfunctions in ILC2KO mice got improved after
mice receiving adoptive transfer of ILC2 or EOS from wild-type (WT) mice, but not ILC2 from IL5-/- mice. We
recently reported high blood EOS count in patients with acute MI and EOS accumulation in mouse heart post-
MI. EOS-deficient ∆dblGATA mice (EOSKO) demonstrated exacerbated cardiac dysfunction and myocardial
fibrosis, all which can be corrected by repopulation of donor EOS from WT mice or by giving mice recombinant
murine EOS cationic protein mEar1 (human ECP ortholog). Similar to the EOSKO mice, DTA-induced depletion
of EOS in iPHIL mice (EOSDTA) also worsened the cardiac function post-MI. Based on these observations, we
hypothesize that ILC2 protect heart from post-MI cardiac dysfunction. One mechanism is to release type-2
cytokines, such as IL5 to promote the development and migration of bone-marrow EOS to the bloodstream and
heart where EOS exert a similar reparative role to that of ILC2 in mitigating ischemic cardiac injury. We
propose two Aims to examine whether and how ILC2 protect heart from MI-induced cardiac dysfunction and to
explore the EOS-mediated reparative mechanisms in response to myocardial ischemic injury.
冠心病仍然是美国死亡的主要原因。尽管降脂治疗取得了成功,
剩余风险依然存在。最近的临床研究支持炎症在CVD中的作用,这是一个长期存在的话题。
基础研究第2组先天性淋巴样细胞(ILC 2)是在肥胖中起重要作用的先天性淋巴细胞
通过促进脂肪细胞褐化并将褐化细胞募集到白色脂肪组织,从而限制肥胖
发展关于ILC 2在CVD中的功能的可用信息有限,尽管移植ILC 2可以促进CVD的发生。
来自ILC 2缺陷小鼠的骨髓促进动脉粥样硬化形成。嗜酸性粒细胞(EOS)在血液中积聚,
过敏或寄生虫感染后的炎症部位。血液EOS计数和EOS阳离子
蛋白质(ECP)水平与主要CV风险因素和CVD患病率和死亡率呈正相关。然而
其他研究报告了主要不良心脏事件患者的血EOS计数和ECP水平降低
和心力衰竭因此,ILC 2和EOS在人类CVD中的作用仍然不确定。我们的初步
研究表明,在心肌梗塞(MI)后,ILC 2在小鼠心脏中积累。ILC 2缺陷
ILC 2KO或白喉毒素A(DTA)诱导的ILC 2耗竭(ILC 2DTA)加重了心脏功能障碍,
心肌梗死后心肌细胞死亡和纤维化。进一步的研究表明,ILC 2缺乏使血液IL 5,
来自ILC 2的必需的2型细胞因子,其控制EOS、树突状细胞(DC)的扩增和迁移,
调节性T细胞(Treg)的血液或炎症部位。流式细胞仪分析显示,
MI后ILC 2KO小鼠的脾、血液或心脏EOS和DC。小鼠重组IL 5的施用
逆转EOS的血液损失,提供了ILC 2活性在减轻心脏病中的机制解释。
这表明EOS和ILC 2在MI后心脏中具有并发的心脏保护作用。
与这一假设相一致,ILC 2KO小鼠心肌梗死后心脏功能障碍加重,
接受来自野生型(WT)小鼠的ILC 2或EOS过继转移,但不接受来自IL 5-/-小鼠的ILC 2过继转移的小鼠。我们
最近报道了急性心肌梗死患者的高血EOS计数和心肌梗死后小鼠心脏中的EOS蓄积,
MI. EOS-缺陷型EoskblGATA小鼠(EOSKO)表现出加重的心功能障碍和心肌梗死。
纤维化,所有这些都可以通过来自WT小鼠的供体EOS的再增殖或通过给予小鼠重组
鼠EOS阳离子蛋白mEar 1(人ECP直系同源物)。与EOSKO小鼠相似,DTA诱导的消耗
iPHIL小鼠中EOS的增加(EOSDTA)也使MI后的心功能恶化。根据这些观察,我们
假设ILC 2保护心脏免于MI后心功能障碍。一种机制是释放第二类
细胞因子,如IL 5,以促进骨髓EOS的发育和迁移到血液中,
其中EOS在减轻缺血性心脏损伤中发挥与ILC 2相似修复作用。我们
提出了两个目的,以检查ILC 2是否以及如何保护心脏免受MI诱导的心功能不全,
探讨EOS介导的心肌缺血损伤修复机制。
项目成果
期刊论文数量(0)
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GUO-PING SHI其他文献
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{{ truncateString('GUO-PING SHI', 18)}}的其他基金
Role of group 2 innate lymphoid cells in myocardial infarction
第 2 组先天淋巴细胞在心肌梗死中的作用
- 批准号:
10540759 - 财政年份:2021
- 资助金额:
$ 68.21万 - 项目类别:
Role of ILC2 and eosinophils in abdominal aortic aneurysm
ILC2 和嗜酸性粒细胞在腹主动脉瘤中的作用
- 批准号:
10322053 - 财政年份:2021
- 资助金额:
$ 68.21万 - 项目类别:
Role of ILC2 and eosinophils in abdominal aortic aneurysm
ILC2 和嗜酸性粒细胞在腹主动脉瘤中的作用
- 批准号:
10538557 - 财政年份:2021
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Role of a novel IL18 binding protein in atherosclerosis
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