Nature Reviews Immunology 11, 158-159 (March 2011) | doi:10.1038/nri2947
Macrophages: Iron macrophages
Nature Reviews Immunology 11, 158-159 (March 2011)
Macrophages contribute to wound healing through the processes of inflammation, matrix deposition and tissue remodelling. However, local accumulation of activated macrophages and macrophage-derived pro-inflammatory factors can also lead to chronic inflammation, which impairs tissue repair. Recent research sheds light on the local factors that influence the contribution of macrophages to wound healing or chronic inflammation.
Sindrilaru et al. first studied the phenotype of human macrophages from chronic venous leg ulcers (CVUs) and investigated the involvement of microenvironmental factors in macrophage-mediated pathogenesis. CVUs are known to contain high levels of iron and, interestingly, the authors found that macrophages in CVUs express high levels of the haemoglobin scavenger receptor CD163, which mediates the endocytosis of haemoglobin–haptoglobin complexes, leading to the accumulation of iron in intracellular stores. In addition, this CD163hi population was shown to express molecules associated with the M1 macrophage subset, such as tumour necrosis factor (TNF), interleukin-12, CC-chemokine receptor 2 and inducible nitric oxide synthase.
The authors hypothesized that the increased iron deposition in CVUs induces an unrestrained pro-inflammatory M1 macrophage population, thereby contributing to chronic inflammation in the lesions. To support this hypothesis they established a mouse model of CVU pathogenesis, in which repeated treatment of mice with iron dextran led to iron accumulation in macrophages. Indeed, iron-loaded mouse macrophages exhibited the same pro-inflammatory M1 phenotype as human CVU macrophages.
High TNF production by this macrophage population was shown to be responsible for impaired wound healing, as TNF neutralization disrupted an autocrine feedback loop that maintains macrophages in an activated pro-inflammatory state and rescued the wound healing response. Similarly, specific macrophage depletion dampened inflammation and improved tissue repair.
Finally, Sindrilaru et al. clarified the mechanism by which unrestrained pro-inflammatory M1 macrophages cause chronic wounds. They showed that iron-induced reactive oxygen and nitrogen species are produced in CVUs and in the skin of iron-loaded mice in a TNF- and macrophage-dependent manner, where they cause oxidative DNA damage and enhance protein nitration. Moreover, the production of reactive oxygen species by iron-loaded macrophages correlates with increased levels of the ageing markers phosphorylated histone H2AX (γH2AX) and INK4A in fibroblasts from CVUs and skin lesions. Therefore, the authors suggest that iron-loaded macrophages induce DNA damage and senescence in skin-resident fibroblasts, thereby impairing their capacity for tissue repair.
So this study describes how iron present in a chronic inflammatory microenvironment promotes TNF-mediated pro-inflammatory macrophage activation, which results in senescence in skin fibroblasts and restrains wound healing. Based on this research, novel targets for the treatment of CVUs and other chronic inflammatory diseases are revealed.
ORIGINAL RESEARCH PAPER
Sindrilaru, A. et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J. Clin. Invest. 7 Feb 2011 (doi: 10.1172/JCI44490)