A growth factor-expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15.
A growth factor-expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15.
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DOI：
10.1084/jem.20210420
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发表时间：
2022-01-03
期刊：
影响因子：
--
通讯作者：
Nagy L
中科院分区：
文献类型：
--
作者：
Patsalos A;Halasz L;Medina-Serpas MA;Berger WK;Daniel B;Tzerpos P;Kiss M;Nagy G;Fischer C;Simandi Z;Varga T;Nagy L
骨骼肌中的再生性炎症通过再生促进程序驱动巨噬细胞特化。生长因子表达的巨噬细胞群体发育，在RXR和PPARγ的控制下产生GDF-15。GDF-15作为一种自分泌和旁分泌因子，协调成肌细胞增殖和髓样细胞侵袭和活性。肌肉再生是多种细胞类型协同作用的结果，这些细胞类型由浸润性单核细胞衍生的巨噬细胞的暂时控制的表型转换驱动。促炎性巨噬细胞转变为通过产生效应物如生长因子来驱动组织修复的表型。我们称之为再生促进程序（RPP）的再生炎症事件的协调序列对于适当的修复至关重要。然而，目前还没有很好地了解如何专门的修复巨噬细胞的身份在转录水平上的RPP的发展，以及如何诱导巨噬细胞衍生的因子协调组织修复。从受损肌肉中分离的血液循环Ly 6Chigh、浸润性炎性Ly 6Chigh和修复性Ly 6Clow巨噬细胞的基于基因表达动力学的聚类，鉴定了TGF-β超家族成员GDF-15作为RPP的组分。骨髓GDF-15是急性无菌损伤后适当肌肉再生所必需的，如功能获得和丧失研究所揭示的。在机制上，GDF-15作用于增殖的成肌细胞和肌肉浸润的骨髓细胞。对Gdf 15表达上游调控因子的表观基因组学分析表明，Gdf 15受核受体RXR/PPARγ的调控。最后，免疫单细胞RNA测序分析显示，Gdf 15与其他已知的肌肉再生相关生长因子共表达，并且它们的表达仅限于修复型巨噬细胞的独特亚群（表达生长因子的巨噬细胞[GFEM]）。
Regenerative inflammation in skeletal muscle drives macrophage specification via a regeneration-promoting program. A growth factor–expressing macrophage population develops, producing GDF-15 under the control of RXR and PPARγ. GDF-15 acts as an autocrine and paracrine factor coordinating myoblast proliferation and myeloid cell invasion and activity. Muscle regeneration is the result of the concerted action of multiple cell types driven by the temporarily controlled phenotype switches of infiltrating monocyte–derived macrophages. Pro-inflammatory macrophages transition into a phenotype that drives tissue repair through the production of effectors such as growth factors. This orchestrated sequence of regenerative inflammatory events, which we termed regeneration-promoting program (RPP), is essential for proper repair. However, it is not well understood how specialized repair-macrophage identity develops in the RPP at the transcriptional level and how induced macrophage–derived factors coordinate tissue repair. Gene expression kinetics–based clustering of blood circulating Ly6Chigh, infiltrating inflammatory Ly6Chigh, and reparative Ly6Clow macrophages, isolated from injured muscle, identified the TGF-β superfamily member, GDF-15, as a component of the RPP. Myeloid GDF-15 is required for proper muscle regeneration following acute sterile injury, as revealed by gain- and loss-of-function studies. Mechanistically, GDF-15 acts both on proliferating myoblasts and on muscle-infiltrating myeloid cells. Epigenomic analyses of upstream regulators of Gdf15 expression identified that it is under the control of nuclear receptors RXR/PPARγ. Finally, immune single-cell RNA-seq profiling revealed that Gdf15 is coexpressed with other known muscle regeneration–associated growth factors, and their expression is limited to a unique subpopulation of repair-type macrophages (growth factor–expressing macrophages [GFEMs]).
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