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  • Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation.

Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation.

Nature communications (2021-11-20)
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, Irina A Udalova
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Phosphatase Inhibitor Cocktail 2, aqueous solution (dark coloration may develop upon storage, which does not affect the activity)
Sigma-Aldrich
Guanosine 5′-triphosphate sodium salt hydrate, ≥95% (HPLC), powder
Sigma-Aldrich
Tris(2-carboxyethyl)phosphine hydrochloride, powder
Roche
cOmplete, Mini, EDTA-free Protease Inhibitor Cocktail, Protease Inhibitor Cocktail Tablets provided in a glass vial, Tablets provided in a glass vial