IFN-γ coordinates macrophage-mediated inflammatory resolution and matrix remodeling in heart regeneration.

Authors

Khai Lone Lim, Yu-Jen Hung, Kaushik Chowdhury, I-Ting Lin, Ke-Hsuan Wei, Bing-Yu Yao, Che-Ming Hu, Shih-Lei Ben Lai

Published in

Cell reports. Volume 45. Issue 11. Pages 118308. Nov 10, 2026. Epub Nov 10, 2026.

Abstract

Heart regeneration requires coordinated immune responses that support tissue remodeling and myocardial renewal. Here, we identify interferon-γ (IFN-γ) as an injury-responsive regulator of macrophage function during zebrafish heart regeneration. Loss of ifng1 disrupted immune cell dynamics, impaired debris clearance and collagen remodeling, reduced cardiomyocyte (CM) protrusion and proliferation, and delayed scar resolution. Cardiac macrophage transcriptomes revealed altered inflammatory and ECM-remodeling programs, including reduced expression of matrix metalloproteinases and increased tissue inhibitors of metalloproteinases (timp4.3) expression. Macrophage-specific blockade of IFN-γ signaling recapitulated key regenerative defects and was associated with similar dysregulation of ECM-remodeling genes. Nanoparticle-mediated timp4.3 silencing reduced its expression in injured adult hearts and FACS-isolated cardiac macrophages, improved collagen remodeling and CM protrusion, and partially rescued CM proliferation and scar resolution in ifng1 mutants. Together, these findings link macrophage IFN-γ signaling to regenerative ECM remodeling and identify Timp4.3 as a functional downstream regulator.

PMID:
43007871
Bibliographic data and abstract were imported from PubMed on 11 Nov 2026.

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