An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice

Area of Science:

• Immunology
• Cell Biology
• Dermatology

Background:

• Uncontrolled macrophage activation is key in chronic inflammatory diseases like atherosclerosis and venous leg ulcers.
• Environmental triggers for persistent macrophage activation and their impact on tissue repair remain unclear.

Purpose of the Study:

• Investigate the role of iron in macrophage activation and chronic inflammation.
• Elucidate the mechanisms by which activated macrophages affect fibroblasts and impair wound healing.

Main Methods:

• Studied human subjects with chronic venous leg ulcers and established a parallel mouse model.
• Analyzed iron overloading in macrophages and its effects on macrophage activation state (M1).
• Assessed the release of TNF-α and hydroxyl radicals and induced fibroblast senescence (p16INK4a-dependent).

Main Results:

• Iron overloading of macrophages induced a proinflammatory M1 activation state in vivo.
• This macrophage population released increased TNF-α and hydroxyl radicals, perpetuating inflammation.
• Macrophage-derived factors induced p16INK4a-dependent fibroblast senescence, impairing wound healing.

Conclusions:

• Identified a novel iron-induced macrophage population driving chronic inflammation and impaired wound healing.
• This macrophage population contributes to fibroblast senescence via TNF-α and hydroxyl radical release.
• Targeting this iron-induced macrophage population presents a potential therapeutic avenue for chronic inflammatory diseases.