Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair

IF 9.4 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Nature cardiovascular research Pub Date : 2024-10-25 DOI:10.1038/s44161-024-00555-4
Sivakumar Ramadoss, Juan Qin, Bo Tao, Nathan E. Thomas, Edward Cao, Rimao Wu, Daniel R. Sandoval, Ann Piermatteo, Kaare V. Grunddal, Feiyang Ma, Shen Li, Baiming Sun, Yonggang Zhou, Jijun Wan, Matteo Pellegrini, Birgitte Holst, Aldons J. Lusis, Philip L.S.M. Gordts, Arjun Deb
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Abstract

Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein initially identified in nonmetastatic melanomas and has been associated with human heart failure; however, its role in cardiac injury and function remains unclear. Here we show that GPNMB expression is elevated in failing human and mouse hearts after myocardial infarction (MI). Lineage tracing and bone-marrow transplantation reveal that bone-marrow-derived macrophages are the main source of GPNMB in injured hearts. Using genetic loss-of-function models, we demonstrate that GPNMB deficiency leads to increased mortality, cardiac rupture and rapid post-MI left ventricular dysfunction. Conversely, increasing circulating GPNMB levels through viral delivery improves heart function after MI. Single-cell transcriptomics show that GPNMB enhances myocyte contraction and reduces fibroblast activation. Additionally, we identified GPR39 as a receptor for circulating GPNMB, with its absence negating the beneficial effects. These findings highlight a pivotal role of macrophage-derived GPNMBs in post-MI cardiac repair through GPR39 signaling. Ramadoss et al. show that bone-marrow-derived macrophages contribute to heart repair following myocardial infarction by secreting GPNMB, which binds to the orphan receptor GPR39 to improve myocyte contractility and reduce fibroblast activation.

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骨髓巨噬细胞衍生的 GPNMB 蛋白与孤儿受体 GPR39 结合,在心脏修复中发挥关键作用。
糖蛋白非转移性黑色素瘤蛋白 B(GPNMB)是一种 I 型跨膜蛋白,最初在非转移性黑色素瘤中被发现,并与人类心力衰竭有关;然而,它在心脏损伤和功能中的作用仍不清楚。在这里,我们发现在心肌梗死(MI)后衰竭的人类和小鼠心脏中,GPNMB的表达升高。系谱追踪和骨髓移植显示,骨髓衍生的巨噬细胞是损伤心脏中 GPNMB 的主要来源。利用基因功能缺失模型,我们证明了 GPNMB 缺乏会导致死亡率上升、心脏破裂和心肌梗死后左心室快速功能障碍。相反,通过病毒递送增加循环中的 GPNMB 水平可改善心肌梗死后的心脏功能。单细胞转录组学研究表明,GPNMB能增强心肌细胞收缩,减少成纤维细胞活化。此外,我们还发现 GPR39 是循环 GPNMB 的受体,缺少 GPR39 就不能产生有益作用。这些发现凸显了巨噬细胞衍生的 GPNMB 通过 GPR39 信号传导在心肌梗死后心脏修复中的关键作用。
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