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Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation.
Ryzhakov, Grigory; Almuttaqi, Hannah; Corbin, Alastair L; Berthold, Dorothée L; Khoyratty, Tariq; Eames, Hayley L; Bullers, Samuel; Pearson, Claire; Ai, Zhichao; Zec, Kristina; Bonham, Sarah; Fischer, Roman; Jostins-Dean, Luke; Travis, Simon P L; Kessler, Benedikt M; Udalova, Irina A.
Afiliación
  • Ryzhakov G; University of Oxford, Kennedy Institute of Rheumatology, Oxford, United Kingdom.
  • Almuttaqi H; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
  • Corbin AL; University of Oxford, Kennedy Institute of Rheumatology, Oxford, United Kingdom.
  • Berthold DL; University of Oxford, Kennedy Institute of Rheumatology, Oxford, United Kingdom.
  • Khoyratty T; University of Oxford, Kennedy Institute of Rheumatology, Oxford, United Kingdom.
  • Eames HL; University of Oxford, Kennedy Institute of Rheumatology, Oxford, United Kingdom.
  • Bullers S; University of Oxford, Kennedy Institute of Rheumatology, Oxford, United Kingdom.
  • Pearson C; University of Oxford, Kennedy Institute of Rheumatology, Oxford, United Kingdom.
  • Ai Z; University of Oxford, Kennedy Institute of Rheumatology, Oxford, United Kingdom.
  • Zec K; University of Oxford, Kennedy Institute of Rheumatology, Oxford, United Kingdom.
  • Bonham S; University of Oxford, Kennedy Institute of Rheumatology, Oxford, United Kingdom.
  • Fischer R; Target Discovery Institute, Nuffield Department of Medicine, Centre for Medicines Discovery, Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, United Kingdom.
  • Jostins-Dean L; Target Discovery Institute, Nuffield Department of Medicine, Centre for Medicines Discovery, Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, United Kingdom.
  • Travis SPL; University of Oxford, Kennedy Institute of Rheumatology, Oxford, United Kingdom.
  • Kessler BM; Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom.
  • Udalova IA; Target Discovery Institute, Nuffield Department of Medicine, Centre for Medicines Discovery, Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, United Kingdom.
Nat Commun ; 12(1): 6702, 2021 11 18.
Article en En | MEDLINE | ID: mdl-34795257
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazinas / Sulfonamidas / Benzamidas / Quinasa 2 de Adhesión Focal / Factores Reguladores del Interferón / Inflamación Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazinas / Sulfonamidas / Benzamidas / Quinasa 2 de Adhesión Focal / Factores Reguladores del Interferón / Inflamación Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Reino Unido