Epithelial HMGB1 Delays Skin Wound Healing and Drives Tumor Initiation by Priming Neutrophils to NETosis

Regenerative responses predispose tissues to tumor initiation by largely unknown mechanisms. High-mobility group box 1 (HMGB1) is a danger-associated molecular pattern contributing to inflammatory pathologies. Here, we show that HMGB1 derived from keratinocytes, but not macrophages, delays cutaneous mechanical wound healing and drives tumor formation, while protecting from epidermal barrier perturbation. In wounds of mice selectively lacking HMGB1 in keratinocytes, a marked reduction in NETosis, a neutrophil-specific cell death program, is observed. Pharmacological targeting of NETosis or HMGB1 during early response to wounding, prevents skin tumorigenesis and accelerates cutaneous regeneration. We observe NETosis in the microenvironment of keratinocyte-derived tumors in mice and lesional and tumor skin of patients suffering from Recessive Dystrophic Epidermolysis Bullosa (RDEB), a disease in which chronic blistering predisposes to tumor formation. We conclude that tumorigenicity of the wound microenvironment depends on epithelial-derived HMGB1 regulating NETosis, thereby establishing a mechanism linking reparative inflammation to tumor initiation.