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：
GUO-PING SHI
金额：
$ 68.21万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
https://reporter.nih.gov/project-details/10365354
关键词：
Acute myocardial infarction Adipocytes Adipose tissue Adoptive Transfer Allergic Apoptosis Basic Science Blood Blood Circulation Bone Marrow Bone Marrow Transplantation Cardiac Cardiac Myocytes Cations Cause of Death Cell Death Cell physiology Cells Clinical Research Coronary heart disease Dendritic Cells Development Diphtheria Toxin Eosinophil cationic protein Event Female Fibroblasts Fibrosis Granulocyte-Macrophage Colony-Stimulating Factor Heart Heart Block Heart Injuries Heart failure Human IL2 gene IL3 Gene IL4 gene IL5 gene Immune In Vitro Inflammation Interleukin-10 Interleukin-13 Lipids Lymphocyte Lymphoid Cell Mediating Mediator of activation protein Molecular Mus Myocardial Myocardial Infarction Myocardial dysfunction Obesity Orthologous Gene Parasitic infection Patients Play Prevalence Protein Biosynthesis Proteins Recombinants Regulatory T-Lymphocyte Reporting Residual state Risk Risk Factors Role Sex Differences Short Interspersed Nucleotide Elements Site Testing Wild Type Mouse alpha Toxin arginase atherogenesis base cardiac repair cardioprotection conditional knockout coronary fibrosis cytokine eosinophil heart function improved ischemic injury male migration mortality obesity development programmed cell death protein 1 protein expression recruit response success

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.

尽管降脂取得了成功，但冠心病仍然是美国死亡的主要原因。残余风险仍然存在。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。第 2 组先天淋巴细胞 (ILC2) 是在肥胖中发挥重要作用的先天淋巴细胞。通过促进脂肪细胞呈米色并将米色细胞募集到白色脂肪组织，从而限制肥胖尽管有关 ILC2 在 CVD 中的功能、移植的信息有限。 ILC2 缺陷小鼠的骨髓促进了血液中嗜酸性粒细胞 (EOS) 的积累。过敏致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）水平与主要心血管危险因素以及心血管疾病患病率和死亡率呈正相关。其他研究报告称，患有严重心脏不良事件的患者的血 EOS 计数和 ECP 水平降低因此，ILC2 和 EOS 在人类 CVD 中的作用仍不确定。研究表明，心肌梗塞 (MI) 缺乏后，ILC2 会在小鼠心脏中积累。 (ILC2KO) 或白喉毒素 A (DTA) 诱导的 ILC2 耗竭 (ILC2DTA) 加剧心脏功能障碍， MI 后心肌细胞死亡和纤维化进一步研究表明，ILC2 缺乏会减弱血液中的 IL5（一种细胞因子）。来自 ILC2 的重要 2 型细胞因子，控制 EOS、树突状细胞 (DC) 和 FACS 分析显示血液或炎症部位的调节性 T 细胞 (Treg) 缺乏。 MI 后 ILC2KO 小鼠的脾脏、血液或心脏 EOS 和 DC 给药小鼠重组 IL5。逆转了血液中 EOS 的损失，为 ILC2 活性减轻心脏骤停提供了机制解释 MI 后功能障碍，提示 EOS 和 ILC2 在 MI 后心脏中同时发挥心脏保护作用。与这一假设相一致的是，ILC2KO 小鼠的 MI 后心功能障碍加剧后得到了改善。接受来自野生型 (WT) 小鼠的 ILC2 或 EOS 过继转移的小鼠，但不接受来自 IL5-/- 小鼠的 ILC2。最近报道了急性心肌梗死患者血中 EOS 计数升高以及小鼠心脏术后 EOS 积聚 MI。EOS 缺陷的 ΔdblGATA 小鼠 (EOSKO) 表现出严重的心脏功能障碍和心肌损伤。纤维化，所有这些都可以通过从 WT 小鼠中重新填充供体 EOS 或通过给予小鼠重组体来纠正鼠 EOS 阳离子蛋白 mEar1（人 ECP 直向同源物）与 EOSKO 小鼠类似，DTA 诱导的消耗。 iPHIL 小鼠中的 EOS (EOSDTA) 也会使 MI 后的心脏功能恶化。保持 ILC2 保护心脏免受 MI 后心功能障碍的一种机制是释放 2 型。细胞因子，例如 IL5，促进骨髓 EOS 的发育和迁移到血液中， EOS 在减轻缺血性心脏损伤方面发挥与 ILC2 相似的修复作用。提出两个目标来检查 ILC2 是否以及如何保护心脏免受 MI 诱导的心功能障碍的影响，并探索 EOS 介导的心肌缺血损伤修复机制。