Myeloid MMP14 Couples Extracellular Proteolysis to Inflammatory and Metabolic Remodeling During Obesity

Authors

• Long J Shao
• Fathima Elizondo
• Feng Gao
• Elizabeth L Lieu
• Bharati Reddi
• Maryam Elizondo
• Iqbal Mahmud
• Kristin Eckel-Mahan
• Philipp E Scherer
• Xin Ge
• Huaizhu Wu
• Sean Hartig
• Kai Sun

Language

English

Publication Date

7-28-2026

Journal

Cell Reports

DOI

10.1016/j.celrep.2026.117681

PMID

42424144

PMCID

PMC13479528

PubMedCentral® Posted Date

8-18-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Macrophages orchestrate tissue remodeling, inflammation, and metabolic dysfunction in obesity, but the role of macrophage-intrinsic extracellular proteolysis in immunometabolic regulation remains unclear. Matrix metalloproteinase-14 (MMP14), a membrane-bound protease, is strongly induced during monocyte-to-macrophage differentiation and further elevated in adipose tissue macrophages from high-fat diet (HFD)-fed mice. Pharmacological inhibition or myeloid-specific deletion of Mmp14 impaired macrophage differentiation, proliferation, migration, phagocytosis, and inflammatory activation in response to obesity-associated adipose tissue signals. Mechanistically, MMP14 promoted inflammatory programming by increasing endotrophin generation and enhancing TLR4-NFκB signaling. MMP14 also reprogrammed macrophage lipid metabolism by suppressing lipolysis and promoting lipid accumulation, altering metabolic communication with neighboring cells. In vivo, myeloid-specific Mmp14 deletion protected mice from HFD-induced insulin resistance, dyslipidemia, hepatic steatosis, adipose inflammation, and fibrosis. These findings identify macrophage MMP14 as a key mediator linking extracellular matrix remodeling with inflammatory and metabolic dysfunction in obesity.

Keywords

Animals, Obesity, Inflammation, Macrophages, Mice, Proteolysis, Matrix Metalloproteinase 14, Diet, High-Fat, Mice, Inbred C57BL, Male, Adipose Tissue, Lipid Metabolism, Signal Transduction, Cell Differentiation, Insulin Resistance, Humans

Published Open-Access

yes

Recommended Citation

Shao, Long J; Elizondo, Fathima; Gao, Feng; et al., "Myeloid MMP14 Couples Extracellular Proteolysis to Inflammatory and Metabolic Remodeling During Obesity" (2026). The Brown Foundation: Institute of Molecular Medicine. 98.
https://digitalcommons.library.tmc.edu/molecular_med/98