The function of the kinase Btk in neutrophil activation is largely unexplored. Here we found that Btk-deficient neutrophils had more production of reactive oxygen species (ROS) after engagement of Toll-like receptors (TLRs) or receptors for tumor-necrosis factor (TNF), which was associated with more apoptosis and was reversed by transduction of recombinant Btk. Btk-deficient neutrophils in the resting state showed hyperphosphorylation and activation of phosphatidylinositol-3-OH kinase (PI(3)K) and protein tyrosine kinases (PTKs) and were in a 'primed' state with plasma membrane-associated GTPase Rac2. In the absence of Btk, the adaptor Mal was associated with PI(3)K and PTKs at the plasma membrane, whereas in control resting neutrophils, Btk interacted with and confined Mal in the cytoplasm. Our data identify Btk as a critical gatekeeper of neutrophil responses.
Bibliographical noteFunding Information:
We thank E. Tsitsikov, E. Rachlin, K. Imai and J. Yata for discussions; all patients who participated in this study; S. Goo Rhee (Ewha Womans University) for antibody to Prx1 phosphorylated at Tyr194; and J.A. Lindquist (Otto-von-Guericke University) for antibody to Cbp (PAG) phosphorylated at Tyr317. Supported by the Ministry of Health, Labour and Welfare of Japan (H. Kane, S.N. and T.M.), the Ministry of Education, Culture, Sports, Science and Technology of Japan (S.M. and T.M.) and by the National Research Foundation of Korea (National Creative Research Initiatives grant to S.-K.L.).
All Science Journal Classification (ASJC) codes
- Immunology and Allergy