scholarly journals Bruton’s tyrosine kinase (BTK) regulates myeloid cell recruitment during acute inflammation.

Author(s):  
Gareth S. D. Purvis ◽  
Haidee Aranda‐Tavio ◽  
Keith M. Channon ◽  
David R. Greaves
Author(s):  
Gareth Purvis ◽  
Haidee Aranda ◽  
Keith Channon ◽  
David Greaves

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.


2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Brooke Benner ◽  
William E. Carson

AbstractBruton’s tyrosine kinase (BTK) inhibitors, drugs utilized in cancer, are being repurposed for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (COVID-19). Recently, BTK inhibitors acalabrutinib and ibrutinib have been found to protect against pulmonary injury in a small group of patients infected with SARS-CoV-2. The high levels of pro-inflammatory cytokines found in the circulation of COVID-19 patients with severe lung disease suggest the involvement of the innate immune system in this process. Understanding the potential mechanism of action of BTK inhibition in SARS-CoV-2 is clearly of importance to determine how acalabrutinib, ibrutinib and possibly other BTK inhibitors may provide protection against lung injury.


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