Role of group 2 innate lymphoid cells in myocardial infarction

在美国，冠心病仍然是导致死亡的主要原因。尽管降脂取得了成功， 剩余风险依然存在。最近的临床研究支持炎症在心血管疾病中的作用，这是一个长期存在的话题 基础研究。第二组先天淋巴样细胞(ILC2)是在肥胖中起重要作用的先天淋巴细胞 通过促进脂肪细胞褐化并将米色细胞招募到白色脂肪组织，从而限制肥胖 发展。关于ILC2在CVD中的作用，现有的信息有限，尽管移植 ILC2基因缺陷小鼠的骨髓促进了动脉粥样硬化的形成。嗜酸性粒细胞(EOS)聚集在血液中或在 过敏性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)水平与主要心血管危险因素、心血管疾病患病率和死亡率呈正相关。还没有 其他研究报告了有主要不良心脏事件的患者的血液EOS计数和ECP水平降低 和心力衰竭。因此，ILC2和EOS在人类CVD中的作用仍未确定。我们的预赛 研究表明，ILC2在心肌梗死(MI)后的小鼠心脏中积聚。ILC2缺乏症 白喉毒素A(ILC2KO)或白喉毒素A(DTA)诱导的ILC2耗竭(ILC2DTA)加剧了心功能不全， 心肌梗死后心肌细胞死亡和纤维化。进一步的研究表明，ILC2缺乏会使血液中的IL5、AND 来自ILC2的必需的2型细胞因子，控制EOS、树突状细胞(DC)的扩张和迁移 调节性T细胞(Treg)进入血流或炎症部位。流式细胞仪分析显示 ILC2KO小鼠心肌梗死后的脾、血或心脏EOS和DC。小鼠重组白介素5的给药 逆转血液中EOS的丢失，为ILC2在缓解心脏疾病中的活性提供机制解释 心肌梗死后功能障碍，提示EOS和ILC2在心肌梗死后心脏中同时发挥心脏保护作用。 与这一假设一致，ILC2KO小鼠心肌梗死后加重的心功能障碍在 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。我们 最近报道了急性心肌梗死患者血液中高EOS计数和小鼠心脏术后EOS积聚。 密西西比。Eos基因缺陷的∆dblGATA小鼠表现出严重的心功能不全和心肌损伤。 纤维化，所有这些都可以通过WT小鼠供体EOS的再繁殖或给予小鼠重组 小鼠EOS阳离子蛋白mEar1(人ECP同源基因)。与EOSKO小鼠相似，DTA诱导的耗竭 IPHIL小鼠EOS(EOSDTA)也可加重心肌梗死后的心功能。基于这些观察，我们 ILC2保护心脏免受心肌梗死后心功能障碍的假说。一种机制是释放类型2 细胞因子，如IL5，促进骨髓EOS的发展和迁移到血液和 在减轻缺血性心脏损伤方面，EOS发挥着与ILC2相似的修复作用。我们 提出两个目标来研究ILC2是否以及如何保护心脏免受心肌梗死引起的心功能障碍的影响 探讨EOS介导的心肌缺血损伤修复机制。

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.