title: An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice.
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.
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
authors.forename: Anca
authors.initials: A
authors.lastname: Sindrilaru
authors.forename: Thorsten
authors.initials: T
authors.lastname: Peters
authors.forename: Stefan
authors.initials: S
authors.lastname: Wieschalka
authors.forename: Corina
authors.initials: C
authors.lastname: Baican
authors.forename: Adrian
authors.initials: A
authors.lastname: Baican
authors.forename: Henriette
authors.initials: H
authors.lastname: Peter
authors.forename: Adelheid
authors.initials: A
authors.lastname: Hainzl
authors.forename: Susanne
authors.initials: S
authors.lastname: Schatz
authors.forename: Yu
authors.initials: Y
authors.lastname: Qi
authors.forename: Andrea
authors.initials: A
authors.lastname: Schlecht
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Weiss
authors.forename: Meinhard
authors.initials: M
authors.lastname: Wlaschek
authors.forename: Cord
authors.initials: C
authors.lastname: Sunderkötter
authors.forename: Karin
authors.initials: K
authors.lastname: Scharffetter-Kochanek
mesh_terms: D000818:Animals; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D007249:Inflammation; D007501:Iron / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010641:Phenotype; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D017665:Hydroxyl Radical; D007501:Iron