{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:04:13Z","timestamp":1792605853977,"version":"4.5.0"},"reference-count":67,"publisher":"American Society for Clinical Investigation","issue":"13","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Novartis","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,8]]},"abstract":"<jats:p>IL-1 receptor-activated kinase 1 (IRAK1) is involved in signal transduction downstream of many TLRs and the IL-1R. Its potential as a drug target for chronic inflammatory diseases is underappreciated. To study its functional role in joint inflammation, we generated a mouse model expressing a functionally inactive IRAK1 (IRAK1 kinase deficient, IRAK1KD), which also displayed reduced IRAK1 protein expression and cell type\u2013specific deficiencies of TLR signaling. The serum transfer model of arthritis revealed a potentially novel role of IRAK1 for disease development and neutrophil chemoattraction exclusively via its activity in nonhematopoietic cells. Consistently, IRAK1KD synovial fibroblasts showed reduced secretion of neutrophil chemoattractant chemokines following stimulation with IL-1\u03b2 or human synovial fluids from patients with rheumatoid arthritis (RA) and gout. Together with patients with RA showing prominent IRAK1 expression in fibroblasts of the synovial lining, these data suggest that targeting IRAK1 may be therapeutically beneficial. As pharmacological inhibition of IRAK1 kinase activity had only mild effects on synovial fibroblasts from mice and patients with RA, targeted degradation of IRAK1 may be the preferred pharmacologic modality. Collectively, these data position IRAK1 as a central regulator of the IL-1\u03b2\u2013dependent local inflammatory milieu of the joints and a potential therapeutic target for inflammatory arthritis.<\/jats:p>","DOI":"10.1172\/jci.insight.149825","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T14:00:56Z","timestamp":1657202456000},"source":"Crossref","is-referenced-by-count":9,"title":["Nonhematopoietic IRAK1 drives arthritis via neutrophil chemoattractants"],"prefix":"10.1172","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4798-3692","authenticated-orcid":true,"given":"Thomas","family":"Hoyler","sequence":"first","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Bannert","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital Basel, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9dric","family":"Andr\u00e9","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian","family":"Beck","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Boulay","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1193-5317","authenticated-orcid":true,"given":"David","family":"Buffet","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadja","family":"Caesar","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Calzascia","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4615-4091","authenticated-orcid":true,"given":"Janet","family":"Dawson","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Kyburz","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital Basel, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Hennze","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Huppertz","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Littlewood-Evans","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1912-4436","authenticated-orcid":true,"given":"Pius","family":"Loetscher","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3074-6925","authenticated-orcid":true,"given":"Kirsten D.","family":"Mertz","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Cantonal Hospital Baselland, Liestal, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Niwa","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gautier","family":"Robert","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S.","family":"Rush","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Ruzzante","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Sarret","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Stein","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismahane","family":"Touil","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9212-7858","authenticated-orcid":true,"given":"Grazyna","family":"Wieczorek","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldine","family":"Zipfel","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Hawtin","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0260-8346","authenticated-orcid":true,"given":"Tobias","family":"Junt","sequence":"additional","affiliation":[{"name":"Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1863"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20170097"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102461"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4906(02)02298-6"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3028"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/art.24552"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201646641"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600583"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.26058"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501874"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.6.2833"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s00393-014-1493-x"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-201851"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/art.39504"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0901181106"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/labmed\/lmy033"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2017.03.018"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600788"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1203268"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1620139114"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1714386114"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80402-1"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20111415"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20042372"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.0655.2001"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.34.21540"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00722-12"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0b013e3283562c3e"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2011.150326"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2018.06.006"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100450"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20080462"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001328"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlr.2021.100117"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202286"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3109\/08916934.2012.719948"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80045-X"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/ni772"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20020439"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/JID.2015.410"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0407247"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0610852103"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/art.23545"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M103815200"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.2147\/JEP.S110702"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.0c00378"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/art.21273"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-018-0112-7"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/nri2094"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1002\/art.40218"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1186\/ar2438"},{"issue":"4","key":"B52","doi-asserted-by":"crossref","DOI":"10.1038\/nrrheum.2013.38","article-title":"Connective tissue diseases: The MECP2\/IRAK1 locus modulates SLE risk via epigenetics","volume":"9","author":"Woodman","year":"2013","journal-title":"Nat Rev Rheumatol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1002\/art.39962"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1213797109"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1002\/art.27470"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.3.1601"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81989-3"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aag3358"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2009.00859.x"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2013.04.001"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.07.018"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1002\/art.41204"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1205099"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1053\/sarh.2001.23701"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kev269"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01520-5"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2015.1081323"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/149825\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T23:31:38Z","timestamp":1779147098000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/149825"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,8]]},"references-count":67,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7,8]]},"published-print":{"date-parts":[[2022,7,8]]}},"alternative-id":["10.1172\/jci.insight.149825"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.149825","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,8]]},"article-number":"e149825"}}