Nonhematopoietic IRAK1 drives arthritis via neutrophil chemoattractants.
Arthritis
Autoimmunity
Innate immunity
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
08 07 2022
08 07 2022
Historique:
received:
22
03
2021
accepted:
03
06
2022
entrez:
8
7
2022
pubmed:
9
7
2022
medline:
12
7
2022
Statut:
epublish
Résumé
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-specific 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-1β 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-1β-dependent local inflammatory milieu of the joints and a potential therapeutic target for inflammatory arthritis.
Identifiants
pubmed: 35801586
pii: 149825
doi: 10.1172/jci.insight.149825
pmc: PMC9310529
doi:
pii:
Substances chimiques
Interleukin-8
0
Interleukin-1 Receptor-Associated Kinases
EC 2.7.11.1
Irak1 protein, mouse
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Références
Arthritis Rheumatol. 2017 Feb;69(2):376-386
pubmed: 28130918
J Immunol. 2003 Mar 15;170(6):2833-42
pubmed: 12626533
Immunity. 1999 Apr;10(4):451-61
pubmed: 10229188
Biochem J. 2017 Jun 6;474(12):2027-2038
pubmed: 28512203
Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):13507-13512
pubmed: 29208712
Nat Immunol. 2014 Dec;15(12):1134-42
pubmed: 25344726
J Biol Chem. 1997 Aug 22;272(34):21540-7
pubmed: 9261174
Nat Immunol. 2002 Apr;3(4):360-5
pubmed: 11896391
Immunol Rev. 2010 Jan;233(1):233-55
pubmed: 20193003
Arthritis Rheum. 2010 Jul;62(7):1921-32
pubmed: 20506316
Curr Opin Pharmacol. 2013 Aug;13(4):565-9
pubmed: 23611654
Semin Arthritis Rheum. 2001 Apr;30(5 Suppl 2):17-20
pubmed: 11357167
Arthritis Rheum. 2005 Sep;52(9):2656-65
pubmed: 16142732
Nat Med. 2021 Nov;27(11):1970-1981
pubmed: 34675383
J Immunol. 2015 Dec 15;195(12):5787-94
pubmed: 26561545
J Exp Med. 2002 Jul 1;196(1):77-85
pubmed: 12093872
J Exp Med. 2005 Mar 21;201(6):915-23
pubmed: 15767370
Mol Immunol. 2017 Jul;87:94-101
pubmed: 28431280
Nat Rev Immunol. 2007 Jun;7(6):429-42
pubmed: 17525752
Cell. 1996 Nov 29;87(5):811-22
pubmed: 8945509
Autoimmunity. 2012 Dec;45(8):602-11
pubmed: 22917079
J Leukoc Biol. 2008 Jan;83(1):64-70
pubmed: 17884993
Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6256-61
pubmed: 19329491
J Immunol. 2001 Aug 1;167(3):1601-8
pubmed: 11466382
Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):E3177-85
pubmed: 23112187
J Immunol. 2011 Feb 1;186(3):1747-54
pubmed: 21191074
J Exp Pharmacol. 2016 Aug 16;8:11-9
pubmed: 27574472
Arthritis Rheum. 2009 Jun;60(6):1661-71
pubmed: 19479877
Curr Opin Rheumatol. 2012 Sep;24(5):499-505
pubmed: 22832823
Sci Immunol. 2017 Apr;2(10):
pubmed: 28649674
Nat Immunol. 2010 May;11(5):373-84
pubmed: 20404851
J Immunol. 2013 Jan 1;190(1):401-10
pubmed: 23225890
Biochem J. 2012 Jan 1;441(1):339-46
pubmed: 22007846
J Immunol. 2011 Jul 1;187(1):538-52
pubmed: 21613614
J Immunol. 2013 Sep 1;191(5):2717-30
pubmed: 23918981
Autoimmun Rev. 2018 Nov;17(11):1138-1149
pubmed: 30217550
Nat Rev Rheumatol. 2018 Dec;14(12):714-726
pubmed: 30420750
Immunity. 1997 Dec;7(6):837-47
pubmed: 9430229
Autoimmun Rev. 2020 Mar;19(3):102461
pubmed: 31917263
J Exp Med. 2008 Dec 22;205(13):2995-3006
pubmed: 19047436
Lab Med. 2019 Jan 1;50(1):34-41
pubmed: 30060033
Oncotarget. 2018 Sep 7;9(70):33416-33439
pubmed: 30279971
Ann Rheum Dis. 2011 Nov;70(11):2029-36
pubmed: 21803750
Immunity. 2010 Aug 27;33(2):266-78
pubmed: 20727790
Am J Physiol Heart Circ Physiol. 2003 Aug;285(2):H597-606
pubmed: 12860565
Arthritis Rheumatol. 2016 Apr;68(4):932-43
pubmed: 26606652
J Invest Dermatol. 2016 Feb;136(2):416-424
pubmed: 26802238
N Engl J Med. 2012 Dec 20;367(25):2396-406
pubmed: 23252526
MAbs. 2015;7(6):1151-60
pubmed: 26284424
Ann Rheum Dis. 2013 Mar;72(3):437-44
pubmed: 22904263
ACS Med Chem Lett. 2020 Oct 09;11(11):2238-2243
pubmed: 33214835
J Lipid Res. 2021;62:100117
pubmed: 34537202
Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2325-30
pubmed: 17277081
Arthritis Rheumatol. 2020 Jun;72(6):919-930
pubmed: 31943941
Arthritis Rheumatol. 2017 Nov;69(11):2114-2123
pubmed: 28732135
J Immunol. 2017 Feb 1;198(3):1308-1319
pubmed: 28003376
Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E514-E523
pubmed: 28069966
Mol Cell Biol. 2012 Oct;32(19):3990-4000
pubmed: 22851693
J Immunol. 2016 Dec 1;197(11):4266-4273
pubmed: 27807192
Arthritis Rheum. 2008 Jul;58(7):1968-73
pubmed: 18576313
Trends Immunol. 2002 Oct;23(10):503-6
pubmed: 12297423
Eur J Immunol. 2017 May;47(5):880-891
pubmed: 28295231
Nat Rev Rheumatol. 2013 Apr;9(4):197
pubmed: 23478492
J Biol Chem. 2001 Aug 3;276(31):29037-44
pubmed: 11397809
Arthritis Res Ther. 2008;10(3):R67
pubmed: 18534016
Rheumatology (Oxford). 2015 Dec;54(12):2134-44
pubmed: 26209330
Z Rheumatol. 2015 Sep;74(7):637-45
pubmed: 25269878