{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:08:23Z","timestamp":1790755703865,"version":"4.1.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T00:00:00Z","timestamp":1666224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Transient receptor potential melastatin 4 (TRPM4) is a Ca<jats:sup>2+<\/jats:sup>-activated, monovalent cation channel that is expressed in a wide range of cells. We previously reported two gain-of-function (GoF) mutations of TRPM4 as the cause of progressive symmetric erythrokeratodermia (PSEK), which shares similar clinical and histopathological features with psoriasis. Using CRISPR\/Cas9 technology, we generated TRPM4<jats:sup>I1029M<\/jats:sup> mice that have the equivalent mutation to one of the two genetic mutations found in human PSEK (equivalent to human TRPM4<jats:sup>I1033M<\/jats:sup>). Using this mutant mice, we examined the effects of TRPM4 GoF at the cellular and phenotypic levels to elucidate the pathological mechanisms underlying PSEK. In the absence of experimental stimulation, TRPM4<jats:sup>I1029M<\/jats:sup> mice did not show a phenotype. When treated with imiquimod (IMQ), however, TRPM4<jats:sup>I1029M<\/jats:sup> mice were predisposed to more severe psoriasiform dermatitis (PsD) than wild-type (WT), which was characterized by greater accumulation of CCR6-expressing \u03b3\u03b4 T cells and higher mRNA levels of <jats:italic>Il17a<\/jats:italic>. In TRPM4<jats:sup>I1029M<\/jats:sup> mice, dendritic cells showed enhanced migration and keratinocytes exhibited increased proliferation. Moreover, a TRPM4 inhibitor, glibenclamide, ameliorated PsD in WT and TRPM4<jats:sup>I1029M<\/jats:sup> mice. Our results indicate elevated TRPM4 activities boosted susceptibility to cutaneous stimuli, likely through elevation of membrane potential and alteration of downstream cellular signaling, resulting in enhanced inflammation. Our results further suggest a possible therapeutic application of TRPM4 inhibitors in psoriasis.<\/jats:p>","DOI":"10.3389\/fimmu.2022.1025499","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T12:17:17Z","timestamp":1666268237000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Gain-of-function of TRPM4 predisposes mice to psoriasiform dermatitis"],"prefix":"10.3389","volume":"13","author":[{"given":"Daisuke","family":"Yamada","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Vu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuesong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenrui","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desiree","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Bloomstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mindy","family":"Huynh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel T.","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.coph.2013.12.003","article-title":"TRPM4 channels in the cardiovascular system","volume":"15","author":"Kruse","year":"2014","journal-title":"Curr Opin Pharmacol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e001625","DOI":"10.1161\/JAHA.114.001625","article-title":"Variants of transient receptor potential melastatin member 4 in childhood atrioventricular block","volume":"5","author":"Syam","year":"2016","journal-title":"J Am Heart Assoc"},{"key":"B3","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/s0092-8674(02)00719-5","article-title":"TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization","volume":"109","author":"Launay","year":"2002","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nature24674","article-title":"Electron cryo-microscopy structure of a human TRPM4 channel","volume":"552","author":"Winkler","year":"2017","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nature24997","article-title":"Structures of the calcium-activated, non-selective cation channel TRPM4","volume":"552","author":"Guo","year":"2017","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar4510","article-title":"Structure of the human TRPM4 ion channel in a lipid nanodisc","volume":"359","author":"Autzen","year":"2018","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1722038115","article-title":"Structure of full-length human TRPM4","volume":"115","author":"Duan","year":"2018","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00269.2010","article-title":"Pharmacological inhibition of TRPM4 hyperpolarizes vascular smooth muscle","volume":"299","author":"Gonzales","year":"2010","journal-title":"Am J Physiol Cell Physiol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/cells7060062","article-title":"Role of the TRPM4 channel in cardiovascular physiology and pathophysiology","volume":"7","author":"Wang","year":"2018","journal-title":"Cells"},{"key":"B10","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.ceca.2006.04.032","article-title":"TRPM4 controls insulin secretion in pancreatic beta-cells","volume":"41","author":"Cheng","year":"2007","journal-title":"Cell Calcium."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-013-1250-z","article-title":"TRPM4 channels in smooth muscle function","volume":"465","author":"Earley","year":"2013","journal-title":"Pflugers Arch"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000880","article-title":"Trpm4 differentially regulates Th1 and Th2 function by altering calcium signaling and NFAT localization","volume":"185","author":"Weber","year":"2010","journal-title":"J Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1648","article-title":"The calcium-activated nonselective cation channel TRPM4 is essential for the migration but not the maturation of dendritic cells","volume":"9","author":"Barbet","year":"2008","journal-title":"Nat Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/ni1441","article-title":"Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4","volume":"8","author":"Vennekens","year":"2007","journal-title":"Nat Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI38292","article-title":"Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I","volume":"119","author":"Kruse","year":"2009","journal-title":"J Clin Invest."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.109.930867","article-title":"Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease","volume":"3","author":"Liu","year":"2010","journal-title":"Circ Cardiovasc Genet"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2018.10.044","article-title":"Gain-of-Function mutations in TRPM4 activation gate cause progressive symmetric erythrokeratodermia","volume":"139","author":"Wang","year":"2019","journal-title":"J Invest Dermatol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1126\/science.1098845","article-title":"TRPM4 regulates calcium oscillations after T cell activation","volume":"306","author":"Launay","year":"2004","journal-title":"Science"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102969","article-title":"The TRPM4 channel controls monocyte and macrophage, but not neutrophil, function for survival in sepsis","volume":"189","author":"Serafini","year":"2012","journal-title":"J Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2008.10.005","article-title":"TRPM4 regulates migration of mast cells in mice","volume":"45","author":"Shimizu","year":"2009","journal-title":"Cell Calcium."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3015","article-title":"TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis","volume":"18","author":"Schattling","year":"2012","journal-title":"Nat Med"},{"key":"B22","doi-asserted-by":"publisher","first-page":"56027","DOI":"10.3791\/56027","article-title":"Isolation and culture of primary mouse keratinocytes from neonatal and adult mouse skin","volume":"125","author":"Li","year":"2017","journal-title":"J Vis Exp"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/0471142727.mb2806s111","article-title":"Assaying cell cycle status using flow cytometry","volume":"111","author":"Kim","year":"2015","journal-title":"Curr Protoc Mol Biol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802999","article-title":"Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23\/IL-17 axis","volume":"182","author":"van der Fits","year":"2009","journal-title":"J Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/art.41882","article-title":"Targeting the CCR6\/CCL20 axis in entheseal and cutaneous inflammation","volume":"73","author":"Shi","year":"2021","journal-title":"Arthritis Rheumatol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2020.11.032","article-title":"Short-term Western diet intake promotes IL-23Mediated skin and joint inflammation accompanied by changes to the gut microbiota in mice","volume":"141","author":"Shi","year":"2021","journal-title":"J Invest Dermatol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1899","article-title":"De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury","volume":"15","author":"Gerzanich","year":"2009","journal-title":"Nat Med"},{"key":"B28","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1016\/j.immuni.2011.08.001","article-title":"Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation","volume":"35","author":"Cai","year":"2011","journal-title":"Immunity"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1101817","article-title":"Epidermal CCR6+ gammadelta T cells are major producers of IL-22 and IL-17 in a murine model of psoriasiform dermatitis","volume":"187","author":"Mabuchi","year":"2011","journal-title":"J Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2018.07.036","article-title":"Is CCR6 required for the development of psoriasiform dermatitis in mice","volume":"139","author":"Yu","year":"2019","journal-title":"J Invest Dermatol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.3390\/ijms21041275","article-title":"Interleukin-17A and keratinocytes in psoriasis","volume":"21","author":"Furue","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1159\/000250927","article-title":"Progressive symmetric erythrokeratodermia","volume":"156","author":"Nir","year":"1978","journal-title":"Dermatologica"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-022-02998-x","article-title":"Glibenclamide directly prevents neuroinflammation by targeting SUR1-TRPM4-Mediated NLRP3 inflammasome activation in microglia","volume":"59","author":"He","year":"2022","journal-title":"Mol Neurobiol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.428219","article-title":"The sulfonylurea receptor 1 (Sur1)-transient receptor potential melastatin 4 (Trpm4) channel","volume":"288","author":"Woo","year":"2013","journal-title":"J Biol Chem"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00055.2019","article-title":"TRPM4 channel inhibitors 9-phenanthrol and glibenclamide differentially decrease guinea pig detrusor smooth muscle whole-cell cation currents and phasic contractions","volume":"318","author":"Malysz","year":"2020","journal-title":"Am J Physiol Cell Physiol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.11.023","article-title":"TRPM4, a Ca2+-activated nonselective cation channel in mouse sino-atrial node cells","volume":"73","author":"Demion","year":"2007","journal-title":"Cardiovasc Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14220","article-title":"Identification of potent and selective small molecule inhibitors of the cation channel TRPM4","volume":"175","author":"Ozhathil","year":"2018","journal-title":"Br J Pharmacol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1025499\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T12:17:22Z","timestamp":1666268242000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1025499\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,20]]},"references-count":37,"alternative-id":["10.3389\/fimmu.2022.1025499"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1025499","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,20]]},"article-number":"1025499"}}