Hypoxia sensing in resident cardiac macrophages regulates monocyte fate specification following ischemic heart injury

IF 9.4 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Farid F. Kadyrov, Andrew L. Koenig, Junedh M. Amrute, Hao Dun, Wenjun Li, Carla J. Weinheimer, Jessica M. Nigro, Attila Kovacs, Andrea L. Bredemeyer, Steven Yang, Shibali Das, Vinay R. Penna, Alekhya Parvathaneni, Lulu Lai, Niklas Hartmann, Benjamin J. Kopecky, Daniel Kreisel, Kory J. Lavine
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Abstract

Myocardial infarction initiates cardiac remodeling and is central to heart failure pathogenesis. Following myocardial ischemia–reperfusion injury, monocytes enter the heart and differentiate into diverse subpopulations of macrophages. Here we show that deletion of Hif1α, a hypoxia response transcription factor, in resident cardiac macrophages led to increased remodeling and overrepresentation of macrophages expressing arginase 1 (Arg1). Arg1+ macrophages displayed an inflammatory gene signature and may represent an intermediate state of monocyte differentiation. Lineage tracing of Arg1+ macrophages revealed a monocyte differentiation trajectory consisting of multiple transcriptionally distinct states. We further showed that deletion of Hif1α in resident cardiac macrophages resulted in arrested progression through this trajectory and accumulation of an inflammatory intermediate state marked by persistent Arg1 expression. Depletion of the Arg1+ trajectory accelerated cardiac remodeling following ischemic injury. Our findings unveil distinct trajectories of monocyte differentiation and identify hypoxia sensing as an important determinant of monocyte differentiation following myocardial infarction. Kadyrov et al. reveal that the hypoxia sensing through HIF1A is an important regulator of monocyte-derived macrophage differentiation, which determines the extent of inflammation and cardiac remodeling after injury.

Abstract Image

缺血性心脏损伤后,常驻心脏巨噬细胞的缺氧感知调节单核细胞的命运分化。
心肌梗死引发心脏重塑,是心力衰竭发病机制的核心。心肌缺血再灌注损伤后,单核细胞进入心脏并分化成不同的巨噬细胞亚群。在这里,我们发现在常驻心脏巨噬细胞中缺失缺氧反应转录因子 Hif1α 会导致重塑增加,并导致表达精氨酸酶 1(Arg1)的巨噬细胞比例过高。Arg1+ 巨噬细胞显示了炎症基因特征,可能代表了单核细胞分化的中间状态。对 Arg1+ 巨噬细胞的系谱追踪显示,单核细胞分化轨迹由多种转录不同的状态组成。我们进一步发现,在驻留的心脏巨噬细胞中删除 Hif1α 会导致这一轨迹的进展受阻,并积累以持续 Arg1 表达为特征的炎症中间状态。Arg1+轨迹的耗竭加速了缺血性损伤后的心脏重塑。我们的研究结果揭示了单核细胞分化的不同轨迹,并确定缺氧感知是心肌梗死后单核细胞分化的重要决定因素。
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CiteScore
5.70
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