Exploring the impact of serine metabolism on cytokine signalling in psoriasis

The skin is a physical and immune barrier protecting the organism against water loss, mechanical insults, and pathogen infection. It has an active metabolic and renewing profile and harbours several cellular types, including keratinocytes and immunocytes. Given its fundamental protective role, skin homeostasis must be tightly regulated; however, this regulation might fail, leading to skin disorders such as skin cancer and inflammatory-mediated skin diseases (ISDs) such as Psoriasis. Psoriasis is an immune-mediated skin disorder affecting around 2% of population worldwide and is characterized by the presence of lesions known as “plaques”, extremely hurting, inflamed, skin portions containing a massive immune cell infiltrate together with keratinocytes displaying aberrant proliferation and differentiation capabilities. As regards disease treatment, the currently available therapeutic options can only provide affected individuals with short-term benefits, due to long-term administration-associated dangerous side effects; plus, they are characterized by continuous need for re-administration in clinical setting, show loss of efficacy over time and are extremely expensive. For these reasons, psoriasis represents to date a socially relevant disease with a strong and ongoing need for new and alternative therapy development. One Carbon Metabolism is an anabolic metabolism able to sustain cellular growth by providing cells with ATP and nucleotides for DNA synthesis, thanks to serine conversion into glycine by the Serine Hydroxy Methyl Transferases (SHMT1 and SHMT2) which fuel the downstream methionine and folate cycle, and is found dysregulated in over proliferative diseases such as cancer. Since psoriasis is characterized by increased cellular proliferation as well, here we focused on the contribution of One Carbon Metabolism to the pathology, studying the effects of serine metabolism modulation on psoriasis features development, first establishing an in vitro psoriatic-like human keratinocyte differentiation model and then using a murine model of psoriasis (IMQ). Using our in vitro psoriatic-like human keratinocyte differentiation model we found that serine metabolism modulation could influence cytokine-induced effects on keratinocyte proliferation and inflammatory mediator production, as well as cytokine pathway activation, while it did not affect keratinocyte differentiation. Moreover, using the in vivo IMQ psoriasis murine model we investigated the role of extracellular serine and glycine deprivation rather than serine catabolism inhibition, on psoriasis-associated hallmarks development, finding a substantial reversion of the IMQ-induced phenotype in mice fed with a serine and glycine deprived diet at histological level but not at molecular level. In conclusion, our in vitro study demonstrated that serine catabolism inhibition, using the SHMTs inhibitors SHIN1, is able to affect psoriatic cytokine-induced effects on keratinocyte proliferation and inflammatory profile, while our in vivo study showed that extracellular serine and glycine deprivation can revert to some extent the development of psoriatic features even in this case by affecting keratinocyte proliferation and thus epidermal thickening. Taken together, data from this work expand the knowledge about the interplay between serine metabolism in keratinocytes and psoriatic clinical features, providing also a more well-rounded perspective on the contribution of serine metabolism to disease development in vivo focusing on extracellular serine availability.