Bruton's TK regulates myeloid cell recruitment during acute inflammation.

BACKGROUND AND PURPOSE

Bruton's TK (BTK) is a non-receptor kinase best known for its role in B lymphocyte development that is critical for proliferation and survival of leukaemic cells in B-cell malignancies. However, BTK is expressed in myeloid cells, particularly neutrophils, monocytes and macrophages where its inhibition has been reported to cause anti-inflammatory properties.

EXPERIMENTAL APPROACH

We explored the role of BTK on 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, pharmacological inhibition of BTK with ibrutinib specifically inhibited neutrophil and Ly6C monocytes, but not Ly6C monocyte recruitment to the peritoneum. X-linked immunodeficient (XID) mice, which have a point mutation in the Btk gene, had reduced neutrophil and monocyte recruitment to the peritoneum following zymosan challenge. 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-κB activity and Akt signalling.

CONCLUSION AND IMPLICATIONS

Our work has identified a new role of BTK in regulating myeloid cell recruitment via two mechanisms, reducing monocyte/macrophages' ability to undergo chemotaxis and reducing chemokine secretion, via reduced NF-κB and Akt activity in tissue resident macrophages.