Pathomechanisms of disturbed wound healing - consequences of S100A9 overexpression for wound healing
Final Report Abstract
The dermal wound healing process is a complex one and requires phase-adapted activation of pro-inflammatory, anti-inflammatory, and tissue-repairing macrophages, which are regulated by signals from the wound environment. Current knowledge indicates that in nonhealing wounds, factors of the inflammatory wound environment lead to dysregulated macrophage activation and induce a persistent dominance of pro-inflammatory macrophages in the wound, preventing the resolution of inflammation. However, the underlying mechanisms of this dysregulation are not yet fully understood. In this project, we demonstrated that the danger molecule S100A9 is strongly stimulated in the epidermis and dermal white adipose tissue (dWAT) during inflammatory responses or after injury. Interestingly, this induction is significantly enhanced and prolonged under obese/diabetic conditions. The binding of S100A9 to its receptor induces IL-1β gene expression in macrophages. In the presence of elevated concentrations of saturated fatty acids (SFA), such as those found in obesity or after a high-fat diet, the inflammasome in macrophages is activated, leading to the release of IL-1β. IL-1β, in turn, enhances S100A9 expression in the epidermis and in dWAT, initiating a self-perpetuating S100A9 response in inflammation under obese conditions. Furthermore, S100A9 impairs proper macrophage activation and polarization, preventing the resolution of skin inflammation. Additionally, dysregulated high expression of S100A9 inhibits the synthesis and deposition of extracellular matrix. In summary, prolonged, dysregulated expression of S100A9, along with elevated concentrations of SFA as found in obesity, contributes to persistent and exacerbated skin inflammation as well as impaired tissue repair. The clinical relevance is evident from the fact that dietary reduction of SFA leads to an improvement of skin inflammation in both mouse models of skin inflammation and in patients with the chronic-inflammatory skin disease, psoriasis. Inhibitors of S100A9 could represent promising therapeutic targets for the treatment of skin inflammation and chronic wounds.
Publications
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Editorial: Metabolic conditions of chronic inflammatory diseases. Frontiers in Immunology, 13.
Saalbach, Anja & Kunz, Manfred
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Overexpression of S100A9 in obesity impairs macrophage differentiation via TLR4-NFkB-signaling worsening inflammation and wound healing. Theranostics, 12(4), 1659-1682.
Franz, Sandra; Ertel, Anastasia; Engel, Kathrin M.; Simon, Jan C. & Saalbach, Anja
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Association of Nutrition, Obesity and Skin. Nutrients, 15(9), 2028.
Saalbach, Anja
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Modulation of Dietary Fatty Acids in an Open-Label Study Improves Psoriasis and Dampens the Inflammatory Activation Status. Nutrients, 15(7), 1698.
Saalbach, Anja; Seitz, Anna-Theresa; Kohlmann, Johannes; Kalweit, Lena; Vogt, Lisa; Selig, Lars; Engel, Kathrin M. & Simon, Jan C.
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Dysregulated S100A9 Expression Impairs Matrix Deposition in Chronic Wounds. International Journal of Molecular Sciences, 25(18), 9980.
Franz, Sandra; Torregrossa, Marta; Anderegg, Ulf; Ertel, Anastasia & Saalbach, Anja
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Dermal White Adipose Tissue–Derived Il-33 Regulates Il-4/13 Expression in Myeloid Cells during Inflammation. Journal of Investigative Dermatology, 145(2), 370-382.
Ertel, Anastasia; Anderegg, Ulf; Franz, Sandra & Saalbach, Anja
