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

Area of Science:

• Cardiovascular Biology
• Immunology
• Cell Biology

Background:

• Macrophages play dual roles in myocardial infarction (MI), contributing to both injury and repair.
• Distinguishing the functions of diverse macrophage populations within the heart is difficult.

Purpose of the Study:

• To elucidate the origins and functions of distinct cardiac macrophage subsets.
• To investigate the role of resident cardiac macrophages in post-MI healing and cardiac function.

Main Methods:

• Fate mapping, parabiosis, and single-cell transcriptomics were employed.
• Macrophage populations were characterized based on TIMD4, LYVE1, MHC-II, and CCR2 expression.
• Inducible depletion of resident macrophages using a Cx3cr1-based system was performed.

Main Results:

• At steady state, TIMD4+LYVE1+MHC-IIloCCR2- resident cardiac macrophages self-renew with minimal blood monocyte contribution.
• Blood monocytes partially or fully replaced other resident macrophage subsets (TIMD4-LYVE1-MHC-IIhiCCR2- and TIMD4-LYVE1-MHC-IIhiCCR2+).
• Ischemic injury reduced resident macrophage numbers, while CCR2+ monocyte-derived macrophages adopted various fates, some resembling resident types.
• TIMD4 marked a subset of resident macrophages, and their depletion impaired cardiac function and promoted adverse remodeling.

Conclusions:

• Cardiac macrophages exhibit functional heterogeneity with distinct origins.
• TIMD4+ resident cardiac macrophages possess a nonredundant, cardioprotective role in the post-MI setting.
• Understanding macrophage subsets is critical for developing targeted therapies for heart disease.