Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction.,Nature Immunology

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Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction.
Nature Immunology ( IF 27.7 ) Pub Date : 2019-Jan-01 , DOI: 10.1038/s41590-018-0272-2
Sarah A Dick _{1,

2} , Jillian A Macklin _{1,

2,

3,

4} , Sara Nejat ₁ , Abdul Momen ₁ , Xavier Clemente-Casares ₁ , Marwan G Althagafi _{1,

4} , Jinmiao Chen _{5,

6} , Crystal Kantores ₁ , Siyavash Hosseinzadeh _{1,

4} , Laura Aronoff _{1,

4} , Anthony Wong _{1,

7} , Rysa Zaman _{1,

7} , Iulia Barbu _{1,

7} , Rickvinder Besla _{1,

4} , Kory J Lavine ₈ , Babak Razani _{8,

9} , Florent Ginhoux _{5,

6} , Mansoor Husain _{1,

2,

3,

4,

10} , Myron I Cybulsky _{1,

4,

10} , Clinton S Robbins _{1,

4,

7,

10} , Slava Epelman _{1,

2,

3,

4,

7,

10}

Affiliation

Macrophages promote both injury and repair after myocardial infarction, but discriminating functions within mixed populations remains challenging. Here we used fate mapping, parabiosis and single-cell transcriptomics to demonstrate that at steady state, TIMD4⁺LYVE1⁺MHC-II^loCCR2^- resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes partially replaced resident TIMD4^-LYVE1^-MHC-II^hiCCR2^- macrophages and fully replaced TIMD4^-LYVE1^-MHC-II^hiCCR2⁺ macrophages, revealing a hierarchy of monocyte contribution to functionally distinct macrophage subsets. Ischemic injury reduced TIMD4⁺ and TIMD4^- resident macrophage abundance, whereas CCR2⁺ monocyte-derived macrophages adopted multiple cell fates within infarcted tissue, including those nearly indistinguishable from resident macrophages. Recruited macrophages did not express TIMD4, highlighting the ability of TIMD4 to track a subset of resident macrophages in the absence of fate mapping. Despite this similarity, inducible depletion of resident macrophages using a Cx3cr1-based system led to impaired cardiac function and promoted adverse remodeling primarily within the peri-infarct zone, revealing a nonredundant, cardioprotective role of resident cardiac macrophages.

中文翻译：

自我更新的常驻心脏巨噬细胞限制了心肌梗塞后的不良重塑。

巨噬细胞促进心肌梗死后的损伤和修复，但混合群体中的区分功能仍然具有挑战性。在这里，我们使用命运图谱、联体共生和单细胞转录组学来证明，在稳定状态下，TIMD4 ⁺ LYVE1 ⁺ MHC-II ^lo CCR2 ^-常驻心脏巨噬细胞在血液单核细胞输入可忽略不计的情况下进行自我更新。单核细胞部分取代了CCR2-^巨噬细胞^中的常驻TIMD4 ^- LYVE1 ^- MHC-II，并完全取代了CCR2 ⁺巨噬细胞中的TIMD4 ^- LYVE1 ^- MHC-II，^揭示了单核细胞对功能不同的巨噬细胞亚群的贡献的层次结构。缺血性损伤降低了 TIMD4 ⁺和 TIMD4 ^-常驻巨噬细胞丰度，而 CCR2 ⁺单核细胞衍生的巨噬细胞在梗塞组织内采取多种细胞命运，包括那些与常驻巨噬细胞几乎无法区分的细胞。招募的巨噬细胞不表达 TIMD4，这凸显了 TIMD4 在没有命运图谱的情况下追踪驻留巨噬细胞子集的能力。尽管存在这种相似性，但使用基于 Cx3cr1 的系统诱导消耗常驻巨噬细胞会导致心脏功能受损，并主要在梗死周围区域促进不良重塑，揭示常驻心脏巨噬细胞的非冗余心脏保护作用。

更新日期：2019-01-25

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