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Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation

Author

Listed:
  • Grigory Ryzhakov

    (University of Oxford, Kennedy Institute of Rheumatology
    Novartis Pharma AG, Novartis Campus)

  • Hannah Almuttaqi

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Alastair L. Corbin

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Dorothée L. Berthold

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Tariq Khoyratty

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Hayley L. Eames

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Samuel Bullers

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Claire Pearson

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Zhichao Ai

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Kristina Zec

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Sarah Bonham

    (University of Oxford)

  • Roman Fischer

    (University of Oxford)

  • Luke Jostins-Dean

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Simon P. L. Travis

    (John Radcliffe Hospital)

  • Benedikt M. Kessler

    (University of Oxford)

  • Irina A. Udalova

    (University of Oxford, Kennedy Institute of Rheumatology)

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.

Suggested Citation

  • Grigory Ryzhakov & Hannah Almuttaqi & Alastair L. Corbin & Dorothée L. Berthold & Tariq Khoyratty & Hayley L. Eames & Samuel Bullers & Claire Pearson & Zhichao Ai & Kristina Zec & Sarah Bonham & Roman, 2021. "Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27038-5
    DOI: 10.1038/s41467-021-27038-5
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    References listed on IDEAS

    as
    1. Yun Zhao & Rachid Zagani & Sung-Moo Park & Naohiro Yoshida & Pankaj Shah & Hans-Christian Reinecker, 2019. "Microbial recognition by GEF-H1 controls IKKε mediated activation of IRF5," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    2. Luke Jostins & Stephan Ripke & Rinse K. Weersma & Richard H. Duerr & Dermot P. McGovern & Ken Y. Hui & James C. Lee & L. Philip Schumm & Yashoda Sharma & Carl A. Anderson & Jonah Essers & Mitja Mitrov, 2012. "Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease," Nature, Nature, vol. 491(7422), pages 119-124, November.
    3. Akinori Takaoka & Hideyuki Yanai & Seiji Kondo & Gordon Duncan & Hideo Negishi & Tatsuaki Mizutani & Shin-ichi Kano & Kenya Honda & Yusuke Ohba & Tak W. Mak & Tadatsugu Taniguchi, 2005. "Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors," Nature, Nature, vol. 434(7030), pages 243-249, March.
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    Cited by:

    1. Chao Yang & Mahesh Bachu & Yong Du & Caroline Brauner & Ruoxi Yuan & Marie Dominique Ah Kioon & Giancarlo Chesi & Franck J. Barrat & Lionel B. Ivashkiv, 2022. "CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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