Hoste, EstherMaueröder, ChristianHove, Lisette vanCatrysse, LeenVikkula, Hanna-KaizaSze, MozesMaes, BastiaanKarjosukarso, DyahMartens, LiesbetGoncalves, AmandaParthoens, EefRoelandt, RiaDeclercq, WimFuentes, IgnaciaPalisson, FrancisGonzalez, SergioSalas-Alanis, Julio C.Boon, LouisHuebener, PeterMulder, Klaas WillemRavichandran, KodiSaeys, YvanSchwabe, Robert FelixLoo, Geert van2020-04-022020-04-022019Cell Reports. 2019 Nov 26;29(9):2689-2701http://hdl.handle.net/11447/3205https://doi.org/10.1016/j.celrep.2019.10.104Regenerative responses predispose tissues to tumor formation by largely unknown mechanisms. High-mobility group box 1 (HMGB1) is a dangerassociated molecular pattern contributing to inflammatory pathologies. We show that HMGB1 derived from keratinocytes, but not myeloid cells, delays cutaneous wound healing and drives tumor formation. In wounds of mice lacking HMGB1 selectively in keratinocytes, a marked reduction in neutrophil extracellular trap (NET) formation is observed. Pharmacological targeting of HMGB1 or NETs prevents skin tumorigenesis and accelerates wound regeneration. HMGB1-dependent NET formation and skin tumorigenesis is orchestrated by tumor necrosis factor (TNF) and requires RIPK1 kinase activity. NETs are present in the microenvironment of keratinocyte-derived tumors in mice and lesional and tumor skin of patients suffering from recessive dystrophic epidermolysis bullosa, a disease in which skin blistering predisposes to tumorigenesis. We conclude that tumorigenicity of the wound microenvironment depends on epithelial-derived HMGB1 regulating NET formation, thereby establishing a mechanism linking reparative inflammation to tumor initiation.18 p.enHMGB1TNFDiabetesEpidermolysis bullosaInnate immunityNeutrophil extracellular trapsSkin inflammationTumor microenvironmentWound healingArticle