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An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice
Anca Sindrilaru, … , Cord Sunderkötter, Karin Scharffetter-Kochanek
Anca Sindrilaru, … , Cord Sunderkötter, Karin Scharffetter-Kochanek
Published February 7, 2011
Citation Information: J Clin Invest. 2011;121(3):985-997. https://doi.org/10.1172/JCI44490.
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Research Article Inflammation

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

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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 p16INK4a-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.

Authors

Anca Sindrilaru, Thorsten Peters, Stefan Wieschalka, Corina Baican, Adrian Baican, Henriette Peter, Adelheid Hainzl, Susanne Schatz, Yu Qi, Andrea Schlecht, Johannes M. Weiss, Meinhard Wlaschek, Cord Sunderkötter, Karin Scharffetter-Kochanek

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Figure 1

Activated macrophages accumulate and persist in CVUs.

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Activated macrophages accumulate and persist in CVUs.
(A) Quantification...
(A) Quantification of CD68+ infiltrating macrophages in NS, AWs at days 1, 2, and 5 after wounding, and CVUs were counted in 10 high-power fields per sample. Results are mean ± SD ratio of CD68+ to total cells counted in the dermis (n = 5). **P < 0.01 versus day-5 AW and NS. (B and C) Representative photomicrographs of skin sections. Activation of macrophages was assessed in NS, AWs, and CVUs by immunostaining of cryosections for the classical activation markers (B) iNOS and (C) TNF-α or the nonclassical activation marker CD163. Nuclei were counterstained with DAPI. Scale bars: 100 μm. Dashed lines indicate the junction between epidermis (e) and dermis. es, eschar; wm, wound margin.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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