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

TLDR

Uncontrolled macrophage activation drives chronic inflammatory diseases, yet the environmental cues that sustain this activation and their effects on fibroblast‑mediated tissue repair remain poorly understood. The study combined human chronic venous leg ulcer samples with a mouse model that closely mimics the disease to investigate macrophage behavior. Iron overload in macrophages generates an unrestrained pro‑inflammatory M1 population that releases TNF‑α and hydroxyl radicals, inducing fibroblast senescence and impairing wound healing, highlighting a potential therapeutic target.

Abstract

Uncontrolled macrophage activation is now considered to be a critical event in the pathogenesis of chronic inflammatory diseases such as atherosclerosis, multiple sclerosis, and chronic venous leg ulcers. However, it is still unclear which environmental cues induce persistent activation of macrophages in vivo and how macrophage-derived effector molecules maintain chronic inflammation and affect resident fibroblasts essential for tissue homeostasis and repair. We used a complementary approach studying human subjects with chronic venous leg ulcers, a model disease for macrophage-driven chronic inflammation, while establishing a mouse model closely reflecting its pathogenesis. Here, we have shown that iron overloading of macrophages--as was found to occur in human chronic venous leg ulcers and the mouse model--induced a macrophage population in situ with an unrestrained proinflammatory M1 activation state. Via enhanced TNF-α and hydroxyl radical release, this macrophage population perpetuated inflammation and induced a p16(INK4a)-dependent senescence program in resident fibroblasts, eventually leading to impaired wound healing. This study provides insight into the role of what we believe to be a previously undescribed iron-induced macrophage population in vivo. Targeting this population may hold promise for the development of novel therapies for chronic inflammatory diseases such as chronic venous leg ulcers.