{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T18:03:59Z","timestamp":1789581839873,"version":"build-2803163510"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"38","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21gm6510008h0001"],"award-info":[{"award-number":["JP21gm6510008h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000646","name":"MEXT | JSPS | Japan Society for the Promotion of Science London","doi-asserted-by":"publisher","award":["24K02887"],"award-info":[{"award-number":["24K02887"]}],"id":[{"id":"10.13039\/501100000646","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,22]]},"abstract":"<jats:p>\n                    Environmental humidity is a key determinant of organismal physiology and homeostasis. Although the genetic basis of humidity-driven responses is well established in invertebrates, the molecular and genetic mechanisms by which mammals respond to low humidity remain unclear. Here, using reconstructed 3D epidermal equivalents and a mouse model, we identify transient receptor potential vanilloid 4 (TRPV4) as an important mediator of low-humidity-induced signaling and transcriptional responses in epidermal keratinocytes. In 3D skin models, low-humidity exposure induced rapid water movement, characterized by enhanced apical water loss and concomitant basal-side water uptake within 90 s, followed by TRPV4-dependent Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx within 3 min. Pharmacological TRPV4 inhibition suppressed MAPK activation at 30 min and both early (3 h) and late (24 h) low-humidity-induced transcriptional changes. Ca\n                    <jats:sup>2+<\/jats:sup>\n                    chelation reduced low-humidity-induced ERK and p38 activation, and ERK inhibition attenuated low-humidity-induced gene expression changes at 3 h. In vivo, acute low-humidity exposure in mice elicited epidermal MAPK activation within 15 min and early transcriptional changes at 3 h, with RNA-sequencing analysis showing enrichment of gene sets associated with cell adhesion or inflammatory responses. These signaling and transcriptomic responses were attenuated in the epidermis of keratinocyte-specific\n                    <jats:italic toggle=\"yes\">Trpv4<\/jats:italic>\n                    conditional knockout mice. Collectively, our findings identify TRPV4 as an important mediator of epidermal\n                    <jats:strike\/>\n                    responses to low-humidity stress, providing a molecular basis for low-humidity-driven signaling in the mammalian epidermis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2603334123","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:37:27Z","timestamp":1789580247000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["TRPV4 mediates low-humidity responses in epidermal keratinocytes"],"prefix":"10.1073","volume":"123","author":[{"given":"Manami","family":"Tanaka","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02kn6nx58","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacology, School of Medicine, Keio University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4529-8695","authenticated-orcid":false,"given":"Shunsuke","family":"Chikuma","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00zdnkx70","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Biotechnology, College of Life Sciences and Medicine, National Tsing-Hua University","place":["Hsinchu, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0593-1974","authenticated-orcid":false,"given":"Mariko","family":"Hara-Chikuma","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02kn6nx58","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacology, School of Medicine, Keio University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-ento-120120-091609"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.247195"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.13301"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijheh.2018.01.015"},{"key":"e_1_3_4_5_2","first-page":"1352","article-title":"Relationship of ambient humidity with cardiovascular diseases: A prospective study of 24, 510 adults in a general population","volume":"37","author":"Zheng C.","year":"2024","unstructured":"C. Zheng , Relationship of ambient humidity with cardiovascular diseases: A prospective study of 24, 510 adults in a general population. Biomed. Environ. Sci. 37, 1352\u20131361 (2024).","journal-title":"Biomed. Environ. 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Hara-Chikuma S. Chikuma Data from \u201cGene expression of human 3D epidermal equivalents exposed to low-humidity stress.\u201d DNA Data Bank of Japan BioProject. https:\/\/ddbj.nig.ac.jp\/search\/entry\/bioproject\/PRJDB40265. Deposited 30 January 2026."},{"key":"e_1_3_4_47_2","unstructured":"M. Hara-Chikuma S. Chikuma Data from \u201cGene expression of mouse epidermis exposed to low versus control humidity in control mice (TRPV4 fl\/fl) and TRPV4 cKO mice.\u201d DNA Data Bank of Japan BioProject. https:\/\/ddbj.nig.ac.jp\/search\/entry\/bioproject\/PRJDB40264. Deposited 30 January 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2603334123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:37:59Z","timestamp":1789580279000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2603334123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,16]]},"references-count":47,"journal-issue":{"issue":"38","published-print":{"date-parts":[[2026,9,22]]}},"alternative-id":["10.1073\/pnas.2603334123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2603334123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,16]]},"assertion":[{"value":"2026-01-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2603334123"}}