Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation.
Nat Commun
; 12(1): 6702, 2021 11 18.
Article
em En
| MEDLINE
| ID: mdl-34795257
ABSTRACT
Interferon regulating factor 5 (IRF5) is a multifunctional regulator of immune responses, and has a key pathogenic function in gut inflammation, but how IRF5 is modulated is still unclear. Having performed a kinase inhibitor library screening in macrophages, here we identify protein-tyrosine kinase 2-beta (PTK2B/PYK2) as a putative IRF5 kinase. PYK2-deficient macrophages display impaired endogenous IRF5 activation, leading to reduction of inflammatory gene expression. Meanwhile, a PYK2 inhibitor, defactinib, has a similar effect on IRF5 activation in vitro, and induces a transcriptomic signature in macrophages similar to that caused by IRF5 deficiency. Finally, defactinib reduces pro-inflammatory cytokines in human colon biopsies from patients with ulcerative colitis, as well as in a mouse colitis model. Our results thus implicate a function of PYK2 in regulating the inflammatory response in the gut via the IRF5 innate sensing pathway, thereby opening opportunities for related therapeutic interventions for inflammatory bowel diseases and other inflammatory conditions.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirazinas
/
Sulfonamidas
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Benzamidas
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Quinase 2 de Adesão Focal
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Fatores Reguladores de Interferon
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Inflamação
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article