{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T16:40:46Z","timestamp":1779900046551,"version":"3.53.1"},"reference-count":27,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T00:00:00Z","timestamp":1723507200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020624","name":"NIHR Nottingham Biomedical Research Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020624","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001003","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001003","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Toll\u2010like receptors 4 (TLR4) and TLR7\/TLR8 play an important role in mediating the inflammatory effects of bacterial and viral pathogens. Interleukin\u20101 receptor\u2010associated kinase 4 (IRAK4) is an important regulator of signalling by toll\u2010like receptor (TLR) and hence is a potential therapeutic target in diseases characterized by increased lung inflammatory signalling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We used an established murine model of acute lung inflammation, and studied human lung tissue ex vivo, to investigate the effects of inhibiting IRAK4 on lung inflammatory pathways.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>We show that TLR4 stimulation produces an inflammatory response characterized by neutrophil influx and tumour necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) production in murine lungs and that these responses are markedly reduced in IRAK4 kinase\u2010dead mice. In addition, we characterize a novel selective IRAK4 inhibitor, BI1543673, and show that this compound can reduce lipopolysaccharide (LPS)\u2010induced airway inflammation in wild\u2010type mice. Additionally, BI1543673 reduced inflammatory responses to both TLR4 and TLR7\/8 stimulation in human lung tissue studied ex vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>These data demonstrate a key role for IRAK4 signalling in lung inflammation and suggest that IRAK4 inhibition has potential utility to treat lung diseases characterized by inflammatory responses driven through TLR4 and TLR7\/8.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16509","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T23:22:20Z","timestamp":1723591340000},"page":"4647-4657","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Interleukin\u20101 receptor\u2010associated kinase 4 (IRAK4) is a critical regulator of inflammatory signalling through toll\u2010like receptors 4 and 7\/8 in murine and human lungs"],"prefix":"10.1111","volume":"181","author":[{"given":"Ian","family":"Sayers","sequence":"first","affiliation":[{"name":"Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute University of Nottingham  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhruma","family":"Thakker","sequence":"additional","affiliation":[{"name":"Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute University of Nottingham  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Billington","sequence":"additional","affiliation":[{"name":"Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute University of Nottingham  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Kreideweiss","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH &amp; Co. KG  Biberach Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc A.","family":"Grundl","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH &amp; Co. KG  Biberach Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Bouyssou","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH &amp; Co. KG  Biberach Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Thamm","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH &amp; Co. KG  Biberach Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Kreuz","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH &amp; Co. KG  Biberach Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian P.","family":"Hall","sequence":"additional","affiliation":[{"name":"Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute University of Nottingham  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,13]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16181"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16180"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c01714"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaz1053"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15868"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600583"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2021-0551OC"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20220625"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.07.012"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13771"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1MD00031D"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151074"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-014-1023-z"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b00231"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113459"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15178"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/iid3.711"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13080"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2222.2006.02633.x"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600788"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000410"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201631"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.10961.1"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.150542"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201242683"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41953"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-0082-8"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.16509","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T02:59:21Z","timestamp":1728356361000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.16509"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,13]]},"references-count":27,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2024,11]]}},"alternative-id":["10.1111\/bph.16509"],"URL":"https:\/\/doi.org\/10.1111\/bph.16509","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,13]]},"assertion":[{"value":"2024-01-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}