Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation

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 Fischer, Luke Jostins-Dean, Simon P. L. Travis, Benedikt M. Kessler and Irina A. Udalova ()
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Grigory Ryzhakov: University of Oxford, Kennedy Institute of Rheumatology
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

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27038-5

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