Inhibition of IRF5 hyperactivation protects from lupus onset and severity.
Autoimmune diseases
Autoimmunity
Immunology
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
01 12 2020
01 12 2020
Historique:
received:
31
01
2018
accepted:
03
09
2020
pubmed:
9
9
2020
medline:
17
2
2021
entrez:
8
9
2020
Statut:
ppublish
Résumé
The transcription factor IFN regulatory factor 5 (IRF5) is a central mediator of innate and adaptive immunity. Genetic variations within IRF5 are associated with a risk of systemic lupus erythematosus (SLE), and mice lacking Irf5 are protected from lupus onset and severity, but how IRF5 functions in the context of SLE disease progression remains unclear. Using the NZB/W F1 model of murine lupus, we show that murine IRF5 becomes hyperactivated before clinical onset. In patients with SLE, IRF5 hyperactivation correlated with dsDNA titers. To test whether IRF5 hyperactivation is a targetable function, we developed inhibitors that are cell permeable, nontoxic, and selectively bind to the inactive IRF5 monomer. Preclinical treatment of NZB/W F1 mice with an inhibitor attenuated lupus pathology by reducing serum antinuclear autoantibodies, dsDNA titers, and the number of circulating plasma cells, which alleviated kidney pathology and improved survival. Clinical treatment of MRL/lpr and pristane-induced lupus mice with an inhibitor led to significant reductions in dsDNA levels and improved survival. In ex vivo human studies, the inhibitor blocked SLE serum-induced IRF5 activation and reversed basal IRF5 hyperactivation in SLE immune cells. We believe this study provides the first in vivo clinical support for treating patients with SLE with an IRF5 inhibitor.
Identifiants
pubmed: 32897883
pii: 120288
doi: 10.1172/JCI120288
pmc: PMC7685739
doi:
pii:
Substances chimiques
Autoantibodies
0
IRF5 protein, human
0
Interferon Regulatory Factors
0
Irf5 protein, mouse
0
Types de publication
Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
6700-6717Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK079310
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR076242
Pays : United States
Organisme : NIAMS NIH HHS
ID : R03 AR054070
Pays : United States
Organisme : NIAMS NIH HHS
ID : R21 AR065959
Pays : United States
Commentaires et corrections
Type : CommentIn
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