Extracellular serine empowers epidermal proliferation and psoriasis-like symptoms
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 di...
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| Veröffentlicht in: | Science advances 2022-12, Vol.8 (50), p.eabm7902-eabm7902 |
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| creator | Cappello, Angela Mancini, Mara Madonna, Stefania Rinaldo, Serena Paone, Alessio Scarponi, Claudia Belardo, Antonio Zolla, Lello Zuccotti, Alessandro Panatta, Emanuele Pallotta, Sabatino Annicchiarico-Petruzzelli, Margherita Albanesi, Cristina Cutruzzolà, Francesca Wang, Lu Jia, Wei Melino, Gerry Candi, Eleonora |
| description | 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 tetrahydrofolate-bound 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. |
| doi_str_mv | 10.1126/sciadv.abm7902 |
| format | Article |
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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 tetrahydrofolate-bound 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.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.abm7902</identifier><identifier>PMID: 36525488</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Cell Proliferation ; Glycine - metabolism ; Glycine - pharmacology ; Glycine Hydroxymethyltransferase - genetics ; Glycine Hydroxymethyltransferase - metabolism ; Humans ; Inflammation - pathology ; Mice ; Psoriasis - pathology ; Serine - metabolism ; Skin Diseases</subject><ispartof>Science advances, 2022-12, Vol.8 (50), p.eabm7902-eabm7902</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c335t-3c991fbd721315f07a6cffadeef7b34ee496048eb1207a0e5ddb6872485750af3</citedby><cites>FETCH-LOGICAL-c335t-3c991fbd721315f07a6cffadeef7b34ee496048eb1207a0e5ddb6872485750af3</cites><orcidid>0000-0003-0682-023X ; 0000-0003-0893-445X ; 0000-0002-3128-3598 ; 0000-0001-9406-3982 ; 0000-0001-8723-9564 ; 0000-0002-3918-3399 ; 0000-0001-8332-4825 ; 0000-0002-3739-8994 ; 0000-0001-5173-4854 ; 0000-0001-5581-7980 ; 0000-0002-7537-6833 ; 0000-0002-4621-2135 ; 0000-0003-0585-6783 ; 0000-0002-4717-4740</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,864,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36525488$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cappello, Angela</creatorcontrib><creatorcontrib>Mancini, Mara</creatorcontrib><creatorcontrib>Madonna, Stefania</creatorcontrib><creatorcontrib>Rinaldo, Serena</creatorcontrib><creatorcontrib>Paone, Alessio</creatorcontrib><creatorcontrib>Scarponi, Claudia</creatorcontrib><creatorcontrib>Belardo, Antonio</creatorcontrib><creatorcontrib>Zolla, Lello</creatorcontrib><creatorcontrib>Zuccotti, Alessandro</creatorcontrib><creatorcontrib>Panatta, Emanuele</creatorcontrib><creatorcontrib>Pallotta, Sabatino</creatorcontrib><creatorcontrib>Annicchiarico-Petruzzelli, Margherita</creatorcontrib><creatorcontrib>Albanesi, Cristina</creatorcontrib><creatorcontrib>Cutruzzolà, Francesca</creatorcontrib><creatorcontrib>Wang, Lu</creatorcontrib><creatorcontrib>Jia, Wei</creatorcontrib><creatorcontrib>Melino, Gerry</creatorcontrib><creatorcontrib>Candi, Eleonora</creatorcontrib><title>Extracellular serine empowers epidermal proliferation and psoriasis-like symptoms</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>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 tetrahydrofolate-bound 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.</description><subject>Animals</subject><subject>Cell Proliferation</subject><subject>Glycine - metabolism</subject><subject>Glycine - pharmacology</subject><subject>Glycine Hydroxymethyltransferase - genetics</subject><subject>Glycine Hydroxymethyltransferase - metabolism</subject><subject>Humans</subject><subject>Inflammation - pathology</subject><subject>Mice</subject><subject>Psoriasis - pathology</subject><subject>Serine - metabolism</subject><subject>Skin Diseases</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkM1Lw0AQxRdRbKm9epQcvaTuR3Y3OUqpH1AQQc9hk52F1WwSdxK1_70preJpBt6bx7wfIZeMrhjj6gZrb-znylRBF5SfkDkXWqZcZvnpv31GlohvlFKWKSVZcU5mQsm9ks_J8-Z7iKaGphkbExOE6FtIIPTdF0RMoPcWYjBN0seu8Q6iGXzXJqa1SY9d9AY9po1_hwR3oR-6gBfkzJkGYXmcC_J6t3lZP6Tbp_vH9e02rYWQQyrqomCuspozwaSj2qjaOWMBnK5EBpAVimY5VIxPGgVpbaVyzbNcakmNEwtyfcidPvsYAYcyeNwXMS10I5ZcSym1zjM-WVcHax07xAiu7KMPJu5KRss9yfJAsjySnA6ujtljFcD-2X-5iR8MfHLu</recordid><startdate>20221216</startdate><enddate>20221216</enddate><creator>Cappello, Angela</creator><creator>Mancini, Mara</creator><creator>Madonna, Stefania</creator><creator>Rinaldo, Serena</creator><creator>Paone, Alessio</creator><creator>Scarponi, Claudia</creator><creator>Belardo, Antonio</creator><creator>Zolla, Lello</creator><creator>Zuccotti, Alessandro</creator><creator>Panatta, Emanuele</creator><creator>Pallotta, Sabatino</creator><creator>Annicchiarico-Petruzzelli, Margherita</creator><creator>Albanesi, Cristina</creator><creator>Cutruzzolà, Francesca</creator><creator>Wang, Lu</creator><creator>Jia, Wei</creator><creator>Melino, Gerry</creator><creator>Candi, Eleonora</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-0682-023X</orcidid><orcidid>https://orcid.org/0000-0003-0893-445X</orcidid><orcidid>https://orcid.org/0000-0002-3128-3598</orcidid><orcidid>https://orcid.org/0000-0001-9406-3982</orcidid><orcidid>https://orcid.org/0000-0001-8723-9564</orcidid><orcidid>https://orcid.org/0000-0002-3918-3399</orcidid><orcidid>https://orcid.org/0000-0001-8332-4825</orcidid><orcidid>https://orcid.org/0000-0002-3739-8994</orcidid><orcidid>https://orcid.org/0000-0001-5173-4854</orcidid><orcidid>https://orcid.org/0000-0001-5581-7980</orcidid><orcidid>https://orcid.org/0000-0002-7537-6833</orcidid><orcidid>https://orcid.org/0000-0002-4621-2135</orcidid><orcidid>https://orcid.org/0000-0003-0585-6783</orcidid><orcidid>https://orcid.org/0000-0002-4717-4740</orcidid></search><sort><creationdate>20221216</creationdate><title>Extracellular serine empowers epidermal proliferation and psoriasis-like symptoms</title><author>Cappello, Angela ; 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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 tetrahydrofolate-bound 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. 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| subjects | Animals Cell Proliferation Glycine - metabolism Glycine - pharmacology Glycine Hydroxymethyltransferase - genetics Glycine Hydroxymethyltransferase - metabolism Humans Inflammation - pathology Mice Psoriasis - pathology Serine - metabolism Skin Diseases |
| title | Extracellular serine empowers epidermal proliferation and psoriasis-like symptoms |
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