Extracellular serine availability regulates inflammatory skin phenotypes

Serine has recently emerged as an important regulator of epidermal cell growth and skin repair, and modulation of serine metabolism through inhibition of Serine Hydroxy-Methyl Transferases (SHMTs) is already known to attenuate the development of skin inflammatory features in vivo. However, the contribution of serine/glycine free diet to inflammatory skin phenotypes, including psoriasis, has not yet been explored. Here, we investigated the role of serine/glycine availability, demonstrating that serine/glycine free diet has an impact on epidermal inflammation. Using a mouse model of inflammation fed either a standard diet or a serine/glycine-deprived diet, followed by topical application of the psoriatic-like inducer IMIQUIMOD (IMQ), we observed a substantial reversal of the IMQ-induced phenotype. This effect was associated with alterations in keratinocyte proliferation and differentiation, as well as inflammatory cell infiltration, leading to reduced epidermal thickening, improved skin organization, and a decrease in CD3⁺ T-lymphocyte infiltration. Taken together, our findings expand current knowledge of the interplay between serine metabolism and the development of skin inflammatory features, providing further evidence for a link between amino acid homeostasis and disease progression. This metabolic connection may be exploited to develop alternative therapeutic strategies for the treatment and management of chronic inflammatory diseases such as psoriasis or atopic dermatitis.