{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T22:43:38Z","timestamp":1788993818419,"version":"build-2803163510"},"reference-count":210,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T00:00:00Z","timestamp":1690329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000090","name":"DoD CDMRP","doi-asserted-by":"publisher","award":["W81XWH-20-1-0081"],"award-info":[{"award-number":["W81XWH-20-1-0081"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The overactivity of keratinocyte cytoplasmic signaling contributes to several cutaneous inflammatory and immune pathologies. An important emerging complement to proteins responsible for this overactivity is signal repression brought about by several proteins and protein complexes with the native role of limiting inflammation. The signaling repression by these proteins distinguishes them from transmembrane receptors, kinases, and inflammasomes, which drive inflammation. For these proteins, defects or deficiencies, whether naturally arising or in experimentally engineered skin inflammation models, have clearly linked them to maintaining keratinocytes in a non-activated state or returning cells to a post-inflamed state after a signaling event. Thus, together, these proteins help to resolve acute inflammatory responses or limit the development of chronic cutaneous inflammatory disease. We present here an integrated set of demonstrated or potentially inflammation-repressive proteins or protein complexes (linear ubiquitin chain assembly complex [LUBAC], cylindromatosis lysine 63 deubiquitinase [CYLD], tumor necrosis factor alpha-induced protein 3-interacting protein 1 [TNIP1], A20, and OTULIN) for a comprehensive view of cytoplasmic signaling highlighting protein players repressing inflammation as the needed counterpoints to signal activators and amplifiers. Ebb and flow of players on both sides of this inflammation equation would be of physiological advantage to allow acute response to damage or pathogens and yet guard against chronic inflammatory disease. Further investigation of the players responsible for repressing cytoplasmic signaling would be foundational to developing new chemical-entity pharmacologics to stabilize or enhance their function when clinical intervention is needed to restore balance.<\/jats:p>","DOI":"10.3390\/ijms241511943","type":"journal-article","created":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T01:27:46Z","timestamp":1690421266000},"page":"11943","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Repressive Control of Keratinocyte Cytoplasmic Inflammatory Signaling"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5441-5533","authenticated-orcid":false,"given":"Liam E.","family":"Carman","sequence":"first","affiliation":[{"name":"Graduate Program in Pharmacology & Toxicology, University of Connecticut, Storrs, CT 06269-3092, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0693-1853","authenticated-orcid":false,"given":"Michael L.","family":"Samulevich","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmacology & Toxicology, University of Connecticut, Storrs, CT 06269-3092, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7440-1948","authenticated-orcid":false,"given":"Brian J.","family":"Aneskievich","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269-3092, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.ceb.2020.09.004","article-title":"Advances in resolving the heterogeneity and dynamics of keratinocyte differentiation","volume":"67","author":"Rice","year":"2020","journal-title":"Curr. 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