Journal article
Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 2.2MB, Terms of use)
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- Publisher copy:
- 10.1038/s41467-021-27038-5
Authors
- Publisher:
- Springer Nature
- Journal:
- Nature Communications More from this journal
- Volume:
- 12
- Article number:
- 6702
- Publication date:
- 2021-11-18
- Acceptance date:
- 2021-10-28
- DOI:
- ISSN:
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2041-1723
- Language:
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English
- Keywords:
- Pubs id:
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1210483
- Local pid:
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pubs:1210483
- Deposit date:
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2021-11-18
Terms of use
- Copyright holder:
- Ryzhakov et al.
- Copyright date:
- 2021
- Rights statement:
- © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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