Bruton's TK regulates myeloid cell recruitment during acute inflammation

Abstract

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 Ly6Chi monocytes, but not Ly6Clo 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.

Molecular Insights into the Impact of Mutations on the Binding Affinity of Targeted Covalent Inhibitors of BTK

“…BTK is an attractive therapeutic target for the treatment of B-cell malignancies. BTK plays a crucial role in myeloid and B-cell development, maturation, and survival . Several targeted covalent inhibitors of BTK have been developed (Figure ), most notably ibrutiniba first-generation BTK inhibitor for treating multiple forms of leukemia and lymphoma.…”

OxPhos in adipose tissue macrophages regulated by BTK enhances their M2-like phenotype and confers a systemic immunometabolic benefit in obesity

“…However, BTK is also highly expressed in myeloid cells, where its functions are less well understood 12,13,14 . BTK plays a central role in macrophage pro-inflammatory signalling regulating the production of cytokines and chemokines 15,16 , and regulating myeloid cell recruitment 17,18 .…”

Ibrutinib-Associated Cardiotoxicity: From the Pharmaceutical to the Clinical

“… 95 , 96 In a zymosan-induced peritonitis model of sterile inflammation, BTK inhibition was correlated with reduced C5a and CCL2 levels, both of which regulate myeloid cell recruitment. 97 As BTK is predominantly expressed in immune cells including macrophages, it is logical to hypothesize that macrophages may actively be involved in ibrutinib-induced arrhythmias. Further studies may be necessary to clarify this potential involvement.…”