Editors' ChoiceImmunology

Btk Keeps Neutrophils Under Control

Science Signaling  27 Mar 2012:
Vol. 5, Issue 217, pp. ec95
DOI: 10.1126/scisignal.2003074

Neutrophils are the earliest responding cells in the innate immune defense against pathogens. They migrate to the site of infection and produce reactive oxygen species (ROS), through the activity of the NADPH oxidase, and antimicrobial peptides to kill invading pathogens. Deficient ROS production leads to life-threatening infections, whereas overproduction of ROS results in tissue damage; thus, the activity of the NADPH oxidase is tightly regulated. Noting that patients with X-linked agammaglobulinemia (XLA), which is caused by a deficiency in the Tec kinase Btk, have neutropenia (reduced numbers of neutrophils), Honda et al. investigated a role for Btk in neutrophil ROS production and apoptosis. Btk is well characterized in its role in mediating the survival and differentiation of B cells, as well as in signaling downstream of Toll-like receptors (TLRs). Neutrophils from XLA patients activated with the stimulant PMA or with various TLR ligands produced more ROS than did similarly stimulated neutrophils from healthy controls. XLA patient neutrophils were more susceptible than were healthy control neutrophils to induction of apoptosis by various stimuli, including tumor necrosis factor (TNF) and PMA, which was blocked by the antioxidant N-acetyl cysteine and rescued with Btk. Western blotting analysis showed that a component of the NADPH oxidase complex and the guanosine triphosphatase Rac2 were already present at the plasma membrane in resting neutrophils from XLA patients (indicating “priming” of the cells), but not healthy controls. XLA patient neutrophils exhibited enhanced activation of protein tyrosine kinases and the serine and threonine kinase PI3K. In resting XLA patient cells, the TLR adaptor protein Mal was associated with PI3K and TKs at the plasma membrane, which led to PI3K activation, whereas in resting control cells, Mal was confined to the cytoplasm through its physical interaction with Btk. Together, these data suggest that Btk restrains the priming of neutrophils and modulates their production of ROS to prevent death by apoptosis.

F. Honda, H. Kano, H. Kanegane, S. Nonoyama, E.-S. Kim, S.-K. Lee, M. Takagi, S. Mizutani, T. Morio, The kinase Btk negatively regulates the production of reactive oxygen species and stimulation-induced apoptosis in human neutrophils. Nat. Immunol. 13, 369–378 (2012). [PubMed]