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