{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:01:13Z","timestamp":1791496873872,"version":"4.3.4"},"reference-count":54,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"918","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K08-HL133380"],"award-info":[{"award-number":["K08-HL133380"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HL155064"],"award-info":[{"award-number":["R01-HL155064"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HL158746"],"award-info":[{"award-number":["R01-HL158746"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HL133721"],"award-info":[{"award-number":["R01-HL133721"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35GM149240"],"award-info":[{"award-number":["R35GM149240"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32HL155005"],"award-info":[{"award-number":["T32HL155005"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2025,12,23]]},"abstract":"<jats:p>\n                    The nuclear factor \u03baB (NF-\u03baB) signaling pathway plays a critical role in activating macrophages in the pathogenesis of many inflammatory diseases. Tissue mechanical properties are important in modulating key cellular proinflammatory responses. Here, we investigated how the mechanosensitive membrane cation channel TRPV4 (transient receptor potential vanilloid 4) limits macrophage proinflammatory responses in bacterial pneumonia. We found that TRPV4 suppressed proinflammatory gene expression in alveolar macrophages in response to\n                    <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                    pneumonia in mice and in response to agonists of various Toll-like receptors (TLRs) in vitro. TRPV4 suppressed proinflammatory gene expression in macrophages by decreasing the activity of the NF-\u03baB subunit p65. Upon stimulation of macrophages with bacterial lipopolysaccharide, a fraction of TRPV4 translocated from the endoplasmic reticulum to the plasma membrane, releasing p65 for nuclear translocation. TRPV4 interacted with p65 through an N-terminal cytoplasmic ankyrin repeat domain (ANKRD) that shares sequence homology with the p65-binding ANKRD of the NF-\u03baB inhibitor I\u03baB\u03b1. Given the diverse roles of TRPV4 and NF-\u03baB in various cell types, our identification of cross-talk between a mechanosensitive channel and p65 in macrophages suggests application to many NF-\u03baB\u2013dependent diseases, such as cancer and atherosclerosis.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.adt1539","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T18:58:16Z","timestamp":1766516296000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":5,"title":["The mechanosensitive channel TRPV4 inhibits pulmonary inflammation by limiting NF-\u03baB signaling in alveolar macrophages"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0102-9572","authenticated-orcid":true,"given":"Adam M.","family":"Boulton","sequence":"first","affiliation":[{"name":"Inflammation and Immunity, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4103-3151","authenticated-orcid":true,"given":"Megan E.","family":"Grund","sequence":"additional","affiliation":[{"name":"Inflammation and Immunity, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Inflammation and Immunity, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2805-4783","authenticated-orcid":true,"given":"Erica M.","family":"Orsini","sequence":"additional","affiliation":[{"name":"Integrated Hospital Care Institute, Department of Pulmonary and Critical Care, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3961-9172","authenticated-orcid":true,"given":"Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"Inflammation and Immunity, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9776-9820","authenticated-orcid":true,"given":"Susamma","family":"Abraham","sequence":"additional","affiliation":[{"name":"Inflammation and Immunity, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9023-4211","authenticated-orcid":true,"given":"Lisa M.","family":"Grove","sequence":"additional","affiliation":[{"name":"Inflammation and Immunity, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4272-1036","authenticated-orcid":true,"given":"Ryan","family":"Musich","sequence":"additional","affiliation":[{"name":"Inflammation and Immunity, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin M.","family":"Snyder","sequence":"additional","affiliation":[{"name":"Inflammation and Immunity, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley","family":"Ricci","sequence":"additional","affiliation":[{"name":"Inflammation and Immunity, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6139-2242","authenticated-orcid":true,"given":"Amber","family":"Cardani-Boulton","sequence":"additional","affiliation":[{"name":"Neuroscience, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0892-7084","authenticated-orcid":true,"given":"Vidula","family":"Vachharajani","sequence":"additional","affiliation":[{"name":"Inflammation and Immunity, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."},{"name":"Integrated Hospital Care Institute, Department of Pulmonary and Critical Care, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3262-3598","authenticated-orcid":true,"given":"Mitchell A.","family":"Olman","sequence":"additional","affiliation":[{"name":"Inflammation and Immunity, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."},{"name":"Integrated Hospital Care Institute, Department of Pulmonary and Critical Care, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5113-543X","authenticated-orcid":true,"given":"Rachel G.","family":"Scheraga","sequence":"additional","affiliation":[{"name":"Inflammation and Immunity, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."},{"name":"Integrated Hospital Care Institute, Department of Pulmonary and Critical Care, Cleveland Clinic Foundation, Cleveland, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix647"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/506430"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200005043421806"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.01.00266001"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-019-0158-0"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12757"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1513\/pats.200508-090JS"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-021-00480-w"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.753940"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-014-1796-8"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110171"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI140299"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2007.09.002"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2012.03559.x"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/1157023"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.142"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2013.09.018"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-47461-5"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1220231110"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5994"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00016.2015"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25021179"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501688"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1901033"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2021.01.026"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-03-705962"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203239"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.04.011"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/sigtrans.2017.23"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.811075"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi300279b"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81698-0"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.05.121"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep14302"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aau1533"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.466797"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00006"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3052"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2017-0154OC"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202005-1989OC"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1308887110"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mattod.2015.01.019"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2020.05.004"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20145644"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00705"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00312-6"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.052548"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1002\/bies.202100288"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.04.033"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.22.8070-8083.2003"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI75331"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.01.049"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-023-01138-4"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens12081053"}],"container-title":["Science Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scisignal.adt1539","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T18:58:24Z","timestamp":1766516304000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scisignal.adt1539"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,23]]},"references-count":54,"journal-issue":{"issue":"918","published-print":{"date-parts":[[2025,12,23]]}},"alternative-id":["10.1126\/scisignal.adt1539"],"URL":"https:\/\/doi.org\/10.1126\/scisignal.adt1539","relation":{},"ISSN":["1945-0877","1937-9145"],"issn-type":[{"value":"1945-0877","type":"print"},{"value":"1937-9145","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,23]]},"assertion":[{"value":"2024-09-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-08","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadt1539"}}