TY - JOUR
T1 - Extracellular serine empowers epidermal proliferation and psoriasis-like symptoms
AU - Cappello, Angela
AU - Mancini, Mara
AU - Madonna, Stefania
AU - Rinaldo, Serena
AU - Paone, Alessio
AU - Scarponi, Claudia
AU - Belardo, Antonio
AU - Zolla, Lello
AU - Zuccotti, Alessandro
AU - Panatta, Emanuele
AU - Pallotta, Sabatino
AU - Annicchiarico-Petruzzelli, Margherita
AU - Albanesi, Cristina
AU - Cutruzzola, Francesca
AU - Wang, Lu
AU - Jia, Wei
AU - Melino, Gerry
AU - Candi, Eleonora
N1 - Publisher Copyright:
© 2022 The Authors.
PY - 2022/12
Y1 - 2022/12
N2 - The contribution of nutrient availability to control epidermal cell proliferation, inflammation, and hyperproliferative diseases remains unknown. Here, we studied extracellular serine and serine/glycine metabolism using human keratinocytes, human skin biopsies, and a mouse model of psoriasis-like disease. We focused on a metabolic enzyme, serine hydroxymethyltransferase (SHMT), that converts serine into glycine and tetrahydrofolatebound one-carbon units to support cell growth. We found that keratinocytes are both serine and glycine auxotrophs. Metabolomic profiling and hypoxanthine supplementation indicated that SHMT silencing/inhibition reduced cell growth through purine depletion, leading to nucleotide loss. In addition, topical application of an SHMT inhibitor suppressed both keratinocyte proliferation and inflammation in the imiquimod model and resulted in a decrease in psoriasis-associated gene expression. In conclusion, our study highlights SHMT2 activity and serine/glycine availability as an important metabolic hub controlling both keratinocyte proliferation and inflammatory cell expansion in psoriasis and holds promise for additional approaches to treat skin diseases.
AB - The contribution of nutrient availability to control epidermal cell proliferation, inflammation, and hyperproliferative diseases remains unknown. Here, we studied extracellular serine and serine/glycine metabolism using human keratinocytes, human skin biopsies, and a mouse model of psoriasis-like disease. We focused on a metabolic enzyme, serine hydroxymethyltransferase (SHMT), that converts serine into glycine and tetrahydrofolatebound one-carbon units to support cell growth. We found that keratinocytes are both serine and glycine auxotrophs. Metabolomic profiling and hypoxanthine supplementation indicated that SHMT silencing/inhibition reduced cell growth through purine depletion, leading to nucleotide loss. In addition, topical application of an SHMT inhibitor suppressed both keratinocyte proliferation and inflammation in the imiquimod model and resulted in a decrease in psoriasis-associated gene expression. In conclusion, our study highlights SHMT2 activity and serine/glycine availability as an important metabolic hub controlling both keratinocyte proliferation and inflammatory cell expansion in psoriasis and holds promise for additional approaches to treat skin diseases.
UR - http://www.scopus.com/inward/record.url?scp=85144193681&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abm7902
DO - 10.1126/sciadv.abm7902
M3 - Journal article
C2 - 36525488
AN - SCOPUS:85144193681
SN - 2375-2548
VL - 8
JO - Science Advances
JF - Science Advances
IS - 50
M1 - abm7902
ER -