Epithelial HMGB1 delays skin wound healing and drives tumor initiation by priming neutrophils to NETosis

This abstract was selected by our Scientific Committee to pitch on the programme in the R2B session (PM).

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, preventing wound-induced skin tumorigenesis. 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.

 

To test the putative beneficial effect of targeting HMGB1 in wound healing applications, we developed hydrogels comprising an HMGB1 inhibitor and analyzed rates of injury repair in normoglycemic and diabetic mice and in pigs. We were able to demonstrate that inhibition of HMGB1 results in accelerated wound healing responses and outperforms current standard-of-care hydrogels.

Authors

Esther Hoste (1,2)
Maarten Mees (3)
Hanna-Kaisa Vikkula (1,2)
Wim Thielemans (3)
Wouter Merckx (4)
Geert van Loo (1,2)

Organisations

Unit for Cellular and Molecular Pathophysiology, VIB Center for Inflammation Research, B-9052 Ghent, Belgium (1)
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (2)
Renewable Materials and Nanotechnology Research Group, Department of Chemical Engineering, KU Leuven, Belgium (3)
Department of Biosystems, KU Leuven, Belgium (4)

Presenting author

Esther Hoste, Postdoctoral researcher, VIB-UGent Center for Inflammation Research
Esther.Hoste@irc.vib-ugent.be
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