Ismahil Mohamed Ameen, Zhou Guihua, Gao Min, Bansal Shyam S, Patel Bindiya, Limdi Nita, Xie Min, Antipenko Sergey, Rokosh Gregg, Hamid Tariq, Prabhu Sumanth D
medRxiv. 2024 Aug 10:2024.08.09.24311769. doi: 10.1101/2024.08.09.24311769.
Fidelity of wound healing after myocardial infarction (MI) is an important determinant of subsequent adverse cardiac remodeling and failure. Macrophages derived from infiltrating Ly6C blood monocytes are a key component of this healing response; however, the importance of other macrophage populations is unclear. Here, using a variety of in vivo murine models and orthogonal approaches, including surgical myocardial infarction, splenectomy, parabiosis, cell adoptive transfer, lineage tracing and cell tracking, RNA sequencing, and functional characterization, we establish in mice an essential role for splenic CD169 Tim4 marginal metallophilic macrophages (MMMs) in post-MI wound healing. Splenic CD169 Tim4 MMMs circulate in blood as Ly6C cells expressing macrophage markers and help populate CD169 Tim4 CCR2 LYVE1 macrophages in the naïve heart. After acute MI, splenic MMMs augment phagocytosis, CCR3 and CCR4 expression, and robustly mobilize to the heart, resulting in marked expansion of cardiac CD169 Tim4 LyVE1 macrophages with an immunomodulatory and pro-resolving gene signature. These macrophages are obligatory for apoptotic neutrophil clearance, suppression of inflammation, and induction of a reparative macrophage phenotype in the infarcted heart. Splenic MMMs are both necessary and sufficient for post-MI wound healing, and limit late pathological remodeling. Liver X receptor-α agonist-induced expansion of the splenic marginal zone and MMMs during acute MI alleviates inflammation and improves short- and long-term cardiac remodeling. Finally, humans with acute ST-elevation MI also exhibit expansion of circulating CD169 Tim4 macrophages. We conclude that splenic CD169 Tim4 MMMs are required for pro-resolving and reparative responses after MI and can be manipulated for therapeutic benefit to limit long-term heart failure.
We establish for the first time that metallophilic marginal macrophages (MMMs) from the spleen, expressing the markers CD169 and Tim4, circulate in blood and traffic to the heart to help maintain the CD169 Tim4 CCR2 LYVE1 macrophage population in the heart. After acute myocardial infarction, splenic MMMs augment cardiac trafficking in response to chemotactic signals, resulting in expansion of CD169 Tim4 macrophages in the heart that play an essential role in post-MI efferocytosis, wound healing and repair while limiting longer term adverse cardiac remodeling. Analogous to mice, humans also exhibit circulating CD169 Tim4 macrophages in the blood that expand after acute ST segment elevation MI. This study highlights the importance of the cardiosplenic axis in acute MI, and the splenic marginal zone, in determining the course and outcome of post-MI LV remodeling.Pharmacological expansion of splenic marginal zone macrophages alleviated post-MI adverse LV remodeling and inflammation, suggesting that splenic modulation is a potential translational therapeutic approach for limiting post-MI inflammation and improving heart repair.
心肌梗死（MI）后伤口愈合的保真度是随后不良心脏重塑和衰竭的重要决定因素。浸润的Ly6C⁺血液单核细胞衍生的巨噬细胞是这种愈合反应的关键组成部分；然而，其他巨噬细胞群体的重要性尚不清楚。在这里，我们使用多种体内小鼠模型和正交方法，包括手术性心肌梗死、脾切除术、联体共生、细胞过继转移、谱系追踪和细胞追踪、RNA测序以及功能表征，在小鼠中确立了脾脏CD169⁺Tim4⁺边缘金属嗜性巨噬细胞（MMMs）在心肌梗死后伤口愈合中的重要作用。脾脏CD169⁺Tim4⁺MMMs作为表达巨噬细胞标志物的Ly6C⁻细胞在血液中循环，并有助于在未受损心脏中填充CD169⁺Tim4⁺CCR2⁻LYVE1⁺巨噬细胞。急性心肌梗死后，脾脏MMMs增强吞噬作用、CCR3和CCR4表达，并强力迁移至心脏，导致心脏CD169⁺Tim4⁺LyVE1⁺巨噬细胞显著扩增，具有免疫调节和促消退基因特征。这些巨噬细胞对于梗死心脏中凋亡中性粒细胞的清除、炎症抑制以及修复性巨噬细胞表型的诱导是必不可少的。脾脏MMMs对于心肌梗死后伤口愈合既是必需的也是充分的，并限制晚期病理重塑。肝X受体-α激动剂在急性心肌梗死期间诱导的脾脏边缘区和MMMs扩增减轻了炎症并改善了短期和长期心脏重塑。最后，急性ST段抬高型心肌梗死患者也表现出循环CD169⁺Tim4⁺巨噬细胞的扩增。我们得出结论，脾脏CD169⁺Tim4⁺MMMs是心肌梗死后促消退和修复反应所必需的，并且可以通过调控以获得治疗益处，从而限制长期心力衰竭。
我们首次证实，来自脾脏的表达CD169和Tim4标志物的金属嗜性边缘巨噬细胞（MMMs）在血液中循环并迁移至心脏，以帮助维持心脏中的CD169⁺Tim4⁺CCR2⁻LYVE1⁺巨噬细胞群体。急性心肌梗死后，脾脏MMMs响应趋化信号增强心脏迁移，导致心脏中CD169⁺Tim4⁺巨噬细胞扩增，这些巨噬细胞在心肌梗死后的胞葬作用、伤口愈合和修复中起重要作用，同时限制长期不良心脏重塑。与小鼠类似，人类在急性ST段抬高型心肌梗死后血液中也表现出循环CD169⁺Tim4⁺巨噬细胞扩增。 本研究强调了心脾轴在急性心肌梗死中的重要性，以及脾脏边缘区在决定心肌梗死后左心室重塑的进程和结果中的重要性。脾脏边缘区巨噬细胞的药理学扩增减轻了心肌梗死后的不良左心室重塑和炎症，表明脾脏调节是一种潜在的转化治疗方法，可用于限制心肌梗死后的炎症并改善心脏修复。
