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Bruton’s tyrosine kinase (BTK) regulates myeloid cell recruitment during acute inflammation
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  • Gareth Purvis,
  • Haidee Aranda,
  • Keith Channon,
  • David Greaves
Gareth Purvis
University of Oxford
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Haidee Aranda
Sir William Dunn School of Pathology
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Keith Channon
University of Oxford
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David Greaves
University of Oxford
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Abstract

Bruton’s tyrosine kinase (BTK) is a non-receptor kinase best known for its role in B lymphocyte development that is critical for proliferation, and survival of leukaemia cells in B cell malignancies. However, BTK is expressed in myeloid cells, particularly monocytes and macrophages where its inhibition has been reported to exhibit anti-inflammatory properties. Therefore, we explored the role of BTK on the migration of myeloid cells in vitro and in vivo. Using the zymosan induced peritonitis model of sterile inflammation we demonstrated that acute (1 h prior to zymosan) inhibition of BTK using a wide range of FDA (Ibrutinib and Acalabrutinib) and non-FDA approved inhibitors (ONO-4059, CNX-774, Olumatinib and LFM-A13) reduced neutrophil and monocyte recruitment. XID mice, which have a point mutation in the Btk gene had reduced neutrophil and monocyte recruitment to the peritoneum following zymosan challenge. To better understand the role of BTK in myeloid cell recruitment we investigated both chemotaxis and chemokine production in monocytes and macrophages. Pharmacological or genetic inhibition of BTK signalling substantially reduced human monocyte and murine macrophage chemotaxis to a range of chemoattractants (complement C5a and CCL2). We also demonstrated that inhibition of BTK in tissue resident macrophages significantly decreases chemokine secretion by reducing NF-kB activity and Akt signalling. Our work has identified a new role of BTK in regulating myeloid cell recruitment via two mechanisms, 1) reducing monocyte/macrophages’ ability to undergo chemotaxis, and 2) reducing chemokine secretion, via reduced NF-kB activity in tissue resident macrophages.

Peer review status:IN REVISION

26 Apr 2021Submitted to British Journal of Pharmacology
29 Apr 2021Assigned to Editor
29 Apr 2021Submission Checks Completed
03 May 2021Reviewer(s) Assigned
23 May 2021Review(s) Completed, Editorial Evaluation Pending
24 May 2021Editorial Decision: Revise Minor