IL-12/IFN-γ axis drives skin wound healing via innate defense mechanisms against bacterial invasion in teleost fish

Abstract

Abstract Objective and design IL-12 is a well-recognized pro-inflammatory cytokine with multi-functions in participating mammalian innate immunity, but little is known regarding the details for protecting skin barrier damage in lower vertebrates. The aim of this study was to evaluate the effects and mechanisms of IL-12 and its key effectors in promoting skin wound repair in teleosts. Material or subjects Recombinant gcIL-12BB (rgcIL-12BB) was employed to investigate IL-12 roles in teleost skin wound healing. Meanwhile, the regulatory effects of rgcIL-12BB on re-epithelialization, inflammation and bacterial clearance at lesion sites were explored. Furthermore, the role of increased IFN-γ and recruited neutrophil in skin wound were uncovered. Finally, the mechanism of neutrophil bacterial clearance triggered by IFN-γ was also elucidated. Results The rgcIL-12BB could promote wound healing, reduce bacterial invasion, and significantly promote epithelial cell proliferation and migration. Moreover, as the main effector of IL-12BB, IFN-γ was observed to exhibit bactericidal activities mainly via recruiting and stimulating autophagic neutrophils in teleosts. In line with findings in mammals, the grass carp guanylate-binding protein 1 (gcGBP1) acts as a downstream effector of the IL-12/IFN-γ axis that interacts with autophagy-related proteins LC3B and P62, which are involved in gcIFN-γ-induced autophagy. Conclusion Collectively, our results highlighted an intrinsic mechanism whereby the IL-12/IFN-γ axis triggers the host's innate defense against bacterial infection, thereby improving skin wound healing in teleosts.