Pathomechanisms of disturbed wound healing - consequences of S100A9 overexpression for wound healing

• Applicants: Professorin Dr. Sandra Franz; Privatdozentin Dr. Anja Saalbach
• Subject Area: Dermatology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445486528

Dermal wound healing is a complex process that requires temporally and spatially coordinated interactions of immune cells and tissue-resident cells. Macrophages play a central role in the coordination of these interactions through phase-adapted expression of pro-inflammatory, anti-inflammatory, and pro-repair phenotypes.The importance of phase-adapted activation of macrophages becomes evident in non-healing wounds such as diabetic ulcers and chronic venous ulcers. In these non-healing wounds, factors of the inflammatory wound environment induce a dysregulated macrophage activation that results in persistence of pro-inflammatory macrophages impeding inflammatory resolution and subsequent tissue repair. The underlying mechanisms of this dysregulation are poorly understood. We have observed that in impaired healing wounds in mice expression of S100A8 and S100A9 proteins is strongly increased and still detectable at the phase of wound healing when inflammatory resolution is normally occurring. S100A8 and S100A9 have a bactericidal and chemotactic effect and stimulate the expression of pro-inflammatory cytokines. In our preliminary work, we show a new function of S100A9 independent of its chemotactic effect. S100A9 inhibits the functional differentiation of anti-inflammatory and pro-repair macrophages and instead induces a pro-inflammatory phenotype.Therefore, we hypothesize that overexpression of S100A8/A9 is one major pathomechanism in non-healing wounds. S100A8/A9 inhibit inflammatory resolution by controlling the functional activation of macrophages and thereby contribute to a prolonged inflammatory response with impaired tissue repair.In order to clarify this working hypothesis, we will elucidate the importance of S100A8/A9 in impaired skin wound healing in animal models and in human samples from patients with non-healing wounds. We will monitor the expression of S100A8/A9 in the course of disturbed wound healing in mice, clarify the importance of overexpression of S100A9 for impaired inflammatory resolution and dermal tissue repair, analyze mechanisms leading to overexpression of S100A8/A9 in pathological conditions and investigate the effects of overexpression of S100A9 on the functional differentiation of macrophages, the underlying mechanisms and the consequences for the interaction with the tissue resident cells.Aim of this project is to clarify the contribution of overexpression of S100A9 in diabetic and obese conditions to the dysregulated wound healing process in chronic wounds and to elucidate underlying mechanisms of overexpression of S100A9 and S100A9-mediated effects. These investigations should reveal whether S100A9 represents a new target for the modulation of impaired wound healing processes.

• DFG Programme: Research Grants