T-Cell-Mediated Inflammatory Response in Neonatal Heart Regeneration

项目概要/摘要 新生小鼠心脏在损伤后具有显著的再生能力， 再生与免疫系统的强有力的激活密切相关。过去十年的研究 专注于先天免疫在新生儿心脏再生过程中的作用，并建立了必要的 巨噬细胞在心肌梗死（MI）后修复和再生过程中的作用。然而，在这方面， 单独的巨噬细胞不足以驱动新生儿再生，因为新生小鼠缺乏适应性免疫， 但保留了先天免疫就不能再生这一结果有力地表明，其他免疫细胞，如 那些参与适应性免疫的细胞也在新生儿心脏再生中发挥作用。在这个项目中，我们的目标是 探讨获得性免疫的作用，特别是CD 4+辅助性T细胞2（Th 2）介导的炎症反应。 作为适应性和先天性免疫信号通路之间的桥梁， 心肌细胞（CM）增殖响应损伤。我们的初步结果表明，Th 2细胞分泌 细胞因子白细胞介素4（IL-4）在MI后第1天的新生小鼠心脏中强烈上调， CM增殖。其受体IL-4 ra在增殖的CM群体中高度表达。我们假设 Th 2细胞介导的IL-4信号传导促进CM增殖和巨噬细胞转化，以及 产生作为新生儿心脏再生中的关键细胞因子途径的亲心因子CCL 24。 了解免疫细胞如何参与新生儿心脏再生将启发 促进成人心脏修复和再生的潜在疗法。

Project Summary/Abstract The neonatal mouse heart possesses a remarkable ability to regenerate following injury and this cardiac regeneration is closely accompanied by robust activation of the immune system. Studies in the last decade have focused on the role of innate immunity during neonatal heart regeneration, and have established the necessary roles for macrophages in the repair and regeneration processes following myocardial infarction (MI). However, macrophages alone are not sufficient to drive neonatal regeneration, as neonatal mice lacking adaptive immunity but retaining innate immunity cannot regenerate. This result strongly suggests that other immune cells such as those involved in adaptive immunity also play a role in neonatal heart regeneration. In this project, we aim to explore the role of adaptive immunity, in particular the CD4+ T helper 2 (Th2) cell-mediated inflammatory response as a bridge between adaptive and innate immune signaling pathways that mediate neonatal cardiomyocyte (CM) proliferation in response to injury. Our preliminary results revealed that the Th2 cell secreted cytokine interleukin 4 (IL-4) is strongly upregulated in neonatal day 1 mouse hearts after MI and can promote CM proliferation. Its receptor IL-4ra is highly expressed in the proliferating CM population. We hypothesize that the Th2 cell-mediated IL-4 signaling promotes CM proliferation and macrophage transformation, as well as generating the cardiotropic factor CCL24 as a critical cytokine pathway in neonatal heart regeneration. Understanding how immune cells participate in neonatal heart regeneration will enlighten the development of potential therapeutics to promote adult heart repair and regeneration in humans.