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

被引:899
作者
Sindrilaru, Anca [1 ]
Peters, Thorsten [1 ]
Wieschalka, Stefan [1 ]
Baican, Corina [2 ]
Baican, Adrian [2 ]
Peter, Henriette [1 ]
Hainzl, Adelheid [1 ]
Schatz, Susanne [1 ]
Qi, Yu [1 ]
Schlecht, Andrea [1 ]
Weiss, Johannes M. [1 ]
Wlaschek, Meinhard [1 ]
Sunderkoetter, Cord [3 ]
Scharffetter-Kochanek, Karin [1 ]
机构
[1] Univ Ulm, Dept Dermatol & Allerg Dis, D-89081 Ulm, Germany
[2] Univ Cluj Napoca, Dept Dermatol & Venerol, Cluj Napoca, Romania
[3] Univ Munster, Dept Dermatol, D-4400 Munster, Germany
关键词
VENOUS LEG ULCERS; HUMAN-SKIN; ALTERNATIVE ACTIVATION; GENE-EXPRESSION; ELEVATED LEVELS; GROWTH-FACTOR; DISEASE; FIBROBLASTS; HYPOTHESIS; INSUFFICIENCY;
D O I
10.1172/JCI44490
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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-alpha and hydroxyl radical release, this macrophage population perpetuated inflammation and induced a pl6(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.
引用
收藏
页码:985 / 997
页数:13
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