Novel regulators of macrophage function to repair sterile inflammation-induced heart injury

项目摘要 从免疫学的角度来看，心脏是一个独特的器官，因为它对损伤的耐受性极低。 和炎症。来自基础和临床研究的越来越多的证据表明，由 无论是急性心肌缺血/再灌注(I/R)还是慢性代谢紊乱(即2型糖尿病)，都起着关键作用 在心力衰竭的发展中起着重要作用，心力衰竭是世界范围内的主要死亡原因。不幸的是，临床试验试图 对心力衰竭炎症的调节要么令人失望，要么前后不一致，目前还没有临床应用。 适用。这一发人深省的事实强化了探索新的心脏炎症介质的迫切需要，并 更好地理解它们潜在的分子/细胞机制。NIGMS资助的主要研究 在过去的5年里，研究者的实验室已经确定了几种新的介体及其相关的信号转导 炎症引发的心脏损伤中控制免疫功能障碍的途径。首先，我们发现有一种 而跨膜蛋白1a(Sectm1a)是一种在髓系免疫细胞中高度表达的蛋白质，是 巨噬细胞(MФ)吞噬I/R心脏中的死亡细胞，从而恢复心功能。第二, 使用2型糖尿病(T2D)小鼠作为慢性低度炎症模型，我们发现Lipocalin 10的丢失 (Lcn10)是Lipocalin超家族中一个特征不佳的成员，它可能导致M-Ф极化不平衡 T2D心形。最后，我们有了一个新的发现，益生菌释放的胞外膜囊泡(EV) 细菌可以促进M-Ф的胞吐作用，但其潜在机制尚不清楚。总而言之，这些多样化和 令人信服的数据为解决无菌研究中的三个关键知识空白提供了强有力的基础 炎症引发的心脏损伤，将通过此Mira应用程序的三个不同项目进行检查：1) 内源性和外源性Sectm1a在M-Ф胞吐中的确切作用和潜在机制 急性心脏I/R对MФS Lcn10表达的影响和/或给予重组Lcn10蛋白(RLcn10) 将MФS转化为抗炎表型以改善T2D小鼠的心功能？3)益生菌可以 细菌EV为基础的纳米药物可用于调节M-Ф的功能或表型以修复I/R或T2D心脏？ 这项拟议的工作通过定义三个新的调节器的角色代表了MФ生物学的范式转变 (Sectm1a、Lcn10和细菌EVS)在MФ功能和极化调节中的作用。我们将利用多种基因 小鼠模型(MФ特异性转基因、全局敲除和杂交模型)和采用的MФ转移模型 要确定在两种无菌炎症条件下的心脏结局(急性心肌I/R引起的强健和 慢性T2D引发的低度炎症)。如果这些项目建成，将极大地推动MФ领域 研究进展，并提供新的治疗选择，以减少无菌炎症引起的心脏损伤， 希望能提高心力衰竭患者的存活率。

Project Summary The heart is a unique organ from an immunological perspective, as it exhibits extremely low tolerance to damage and inflammation. Growing evidence from basic and clinical research suggests that sterile inflammation, triggered by either acute myocardial ischemia/reperfusion (I/R) or chronic metabolic disorders (i.e., type-2 diabetes), plays a critical role in the development of heart failure, a leading cause of death worldwide. Unfortunately, clinical trials attempting to modulate inflammation in heart failure have been either disappointing or inconsistent and none are yet clinically applicable. This sobering fact reinforces the urgent need to explore new mediators of cardiac inflammation and to better understand their underlying molecular/cellular mechanisms. The studies supported by NIGMS in the principal investigator’s laboratory over the past 5 years have identified several novel mediators and their associated signaling pathways to control immune dysfunction in inflammation-triggered heart injury. First, we discovered that secreted and transmembrane 1a (Sectm1a), a protein highly expressed in immune cells of myeloid lineage, is essential for macrophage (MФ) efferocytosis to clear dead cells from I/R hearts and thereby, restoring cardiac function. Second, using type-2 diabetic (T2D) mice as a chronic low-grade inflammation model, we identified that loss of lipocalin 10 (Lcn10), a poorly characterized member of the lipocalin superfamily, could cause an imbalanced MФ polarization in T2D hearts. Finally, we have made a novel finding that extracellular membrane vesicles (EVs) released by probiotic bacteria can promote MФ efferocytosis, but the underlying mechanism is unclear. Together, these diverse and compelling data provide a strong basis to address three critical knowledge gaps in the study of sterile inflammation-triggered heart injury, which will be examined by three different projects of this MIRA application: 1) what are exact roles and underlying mechanisms of endogenous and exogenous Sectm1a in MФ efferocytosis during acute cardiac I/R? 2) can elevation of Lcn10 in MФs and/or administration of recombinant Lcn10 protein (rLcn10) drive MФs to an anti-inflammatory phenotype for improving cardiac function in T2D mice? and 3) can a probiotic bacterial EV-based nano-drug be developed to modulate MФ function or phenotype for repairing I/R or T2D hearts? The proposed work represents a paradigm shift in MФ biology by defining the roles of three novel modulators (Sectm1a, Lcn10, and bacterial EVs) in the regulation of MФ function and polarization. We will utilize multiple genetic mouse models (MФ-specific transgenic, global knockout, and intercross models) and an adoptive MФ transfer model to determine cardiac outcomes in two sterile inflammation conditions (acute myocardial I/R-induced robust and chronic T2D-triggered low-grade inflammation). These projects, if completed, will significantly push the field of MФ research forward, and offer new therapeutic options for reducing sterile inflammation-caused heart injury, with the hope of improving heart failure patient survival.