{"doi":"10.1101/2021.01.09.426056","title":"Epidermal TRPV4 ion channels regulate UVB induced sunburn by triggering inflammmasome activation and ERK signaling","abstract":"ABSTRACT Skin inflammation is an evolutionary-honed protective mechanism that serves to clear noxious cues and irritants and initiate regeneration. Calcium-permeable transient-receptor-potential (TRP) ion channels have critical functions in sensory transduction which is sensitized in skin inflammation. Skin sensory transduction relies on skin-innervating sensory neurons in the dorsal root ganglion (DRG), but also on innervated keratinocytes (KC). The multimodally-activated TRPV4 is robustly expressed in KC, where it can readily be activated by Ultraviolet-B (UVB). Our goal was to deconstruct keratinocyte TRPV4-mediated signaling, specifically how TRPV4 can facilitate inflammatory injury, thus lowering pain thresholds and rendering KC into pain-generator cells. We wanted to uncover the effect of TRPV4-mediated signaling on UVB-induced inflammasome activation in KC given the powerful impact of the activated inflammasome on pro-inflammatory/pro-algesic secretory signaling, using mouse models and cultured human KC. In mice, our evidence suggests that TRPV4 functions as calcium-permeable channel upstream of the KC inflammasome. Furthermore, we found that UVB induced activation of TRPV4 caused rapid - within minutes - E xtracellular Signal R egulated K inase (ERK) phosphorylation, caspase-1 activation and Interleukin-1ß (IL-1ß) secretion. In human primary KC we demonstrated that UVB induced secretion of IL-1ß was dependent on the NLR family pyrin domain containing 1 (NLRP1) inflammasome. Direct chemical TRPV4 activation could also activate NLRP1 and to lesser extent NLPR3. Building on our previous work, we now define at increased resolution TPRV4-dependent forefront signaling mechanisms in KC in response to UVB, showing TRPV4 upstream of the NLRP1 inflammasome, subsequent rapid ERK activation and pro-inflammatory/pro-algesic secretory function.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":222829,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9618,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":824084,"name":"Shinbe Choi","orcid":"0009-0006-3505-4318","position":1,"is_corresponding":false},{"id":824512,"name":"Gene Moon","orcid":null,"position":2,"is_corresponding":false},{"id":57749,"name":"Jennifer Zhang","orcid":"0000-0002-4485-1750","position":3,"is_corresponding":false},{"id":539414,"name":"Yong Chen","orcid":"0000-0001-8824-7187","position":4,"is_corresponding":false},{"id":247227,"name":"Wolfgang Liedtke","orcid":"0000-0003-4166-5394","position":5,"is_corresponding":false},{"id":641623,"name":"Carlene Moore","orcid":null,"position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T23:54:07.287704Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}