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\nits role in B lymphocyte development that is critical for proliferation,\nand survival of leukaemia cells in B cell malignancies. However, BTK is\nexpressed in myeloid cells, particularly monocytes and macrophages where\nits inhibition has been reported to exhibit anti-inflammatory\nproperties. Therefore, we explored the role of BTK on the migration of\nmyeloid cells in vitro and in vivo. Using the zymosan induced\nperitonitis model of sterile inflammation we demonstrated that acute (1\nh prior to zymosan) inhibition of BTK using a wide range of FDA\n(Ibrutinib and Acalabrutinib) and non-FDA approved inhibitors (ONO-4059,\nCNX-774, Olumatinib and LFM-A13) reduced neutrophil and monocyte\nrecruitment. XID mice, which have a point mutation in the Btk gene had\nreduced neutrophil and monocyte recruitment to the peritoneum following\nzymosan challenge. To better understand the role of BTK in myeloid cell\nrecruitment we investigated both chemotaxis and chemokine production in\nmonocytes and macrophages. Pharmacological or genetic inhibition of BTK\nsignalling substantially reduced human monocyte and murine macrophage\nchemotaxis to a range of chemoattractants (complement C5a and CCL2). We\nalso demonstrated that inhibition of BTK in tissue resident macrophages\nsignificantly decreases chemokine secretion by reducing NF-kB activity\nand Akt signalling. Our work has identified a new role of BTK in\nregulating myeloid cell recruitment via two mechanisms, 1) reducing\nmonocyte/macrophages’ ability to undergo chemotaxis, and 2) reducing\nchemokine secretion, via reduced NF-kB activity in tissue resident\nmacrophages.