LAUSR

BACKGROUND AND PURPOSE 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 leukemic cells in B cell malignancies. However, BTK is expressed in myeloid cells, particularly neutrophils, monocytes and macrophages where its inhibition has been reported to exhibit anti-inflammatory properties. EXPERIMENTAL APPROACH We explored the role of BTK on the migration of myeloid cells (neutrophils, monocytes and macrophages); in vitro using chemotaxis assays and in vivo using zymosan induced peritonitis as model systems. KEY RESULTS Using the zymosan induced peritonitis model of sterile inflammation we demonstrated that acute inhibition of BTK prior to zymosan challenge reduced phosphorylation of BTK in circulating neutrophils and monocytes. Moreover, we demonstrated that pharmacological inhibition of BTK with ibrutinib specifically inhibits neutrophil and Ly6Chi monocytes, but not Ly6Clo monocyte recruitment to the peritoneum. 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 macrophages. Pharmacological or genetic inhibition of BTK signalling substantially reduced human monocyte and murine macrophage chemotaxis, to a range of clinically relevant chemoattractants (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. CONCLUSION AND IMPLICATIONS 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 and Akt activity in tissue resident macrophages.