Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction

Nat Immunol. 2019 Jan;20(1):29-39. doi: 10.1038/s41590-018-0272-2. Epub 2018 Dec 11.

Abstract

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-IIloCCR2- resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes partially replaced resident TIMD4-LYVE1-MHC-IIhiCCR2- macrophages and fully replaced TIMD4-LYVE1-MHC-IIhiCCR2+ 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1 / metabolism
  • Cell Differentiation
  • Cell Lineage
  • Cell Self Renewal
  • Gene Expression Profiling
  • Histocompatibility Antigens Class II / metabolism
  • Macrophages / physiology*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Myocardial Infarction / immunology*
  • Myocardium / pathology*
  • Parabiosis
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / metabolism
  • Single-Cell Analysis
  • Ventricular Remodeling
  • Vesicular Transport Proteins / metabolism

Substances

  • CX3C Chemokine Receptor 1
  • Ccr2 protein, mouse
  • Cx3cr1 protein, mouse
  • Histocompatibility Antigens Class II
  • LYVE1 protein, mouse
  • Membrane Proteins
  • Receptors, CCR2
  • TIM-4 protein, mouse
  • Vesicular Transport Proteins