Myeloid MMP14 couples extracellular proteolysis to inflammatory and metabolic remodeling during obesity

Area of Science:

• Immunology
• Metabolic disease
• Cell biology

Background:

• Macrophages play a critical role in obesity-associated tissue remodeling and inflammation.
• The function of macrophage-intrinsic extracellular proteolysis in immunometabolic regulation during obesity is not well understood.

Purpose of the Study:

• To investigate the role of matrix metalloproteinase-14 (MMP14) in macrophage function and its contribution to obesity-related metabolic dysfunction.

Main Methods:

• Studied MMP14 expression during monocyte-to-macrophage differentiation and in adipose tissue macrophages from high-fat diet (HFD)-fed mice.
• Utilized pharmacological inhibition and myeloid-specific deletion of Mmp14 in mouse models.
• Assessed macrophage functions including differentiation, proliferation, migration, phagocytosis, and inflammatory activation.
• Analyzed signaling pathways (TLR4-NFκB) and lipid metabolism.
• Evaluated in vivo effects on HFD-induced metabolic disorders, inflammation, and fibrosis.

Main Results:

• MMP14 expression is upregulated during macrophage differentiation and in adipose tissue macrophages from HFD-fed mice.
• MMP14 inhibition or deletion impaired macrophage functions and inflammatory responses.
• MMP14 promotes inflammation via endotrophin generation and TLR4-NFκB signaling.
• MMP14 alters macrophage lipid metabolism, suppressing lipolysis and promoting lipid accumulation.
• Myeloid-specific Mmp14 deletion protected mice from HFD-induced insulin resistance, dyslipidemia, hepatic steatosis, adipose inflammation, and fibrosis.

Conclusions:

• Macrophage MMP14 is a key mediator linking extracellular matrix remodeling to inflammatory and metabolic dysfunction in obesity.
• Targeting MMP14 in macrophages represents a potential therapeutic strategy for managing obesity-related metabolic diseases.