Editors' ChoiceLung Disease

A Damaging Survival Signal

Sci. Signal.  14 May 2013:
Vol. 6, Issue 275, pp. ec105
DOI: 10.1126/scisignal.2004319

Neutrophils are very short-lived (surviving hours in blood and a few days in tissue) inflammatory cells of the innate immune system. Patients with chronic obstructive pulmonary disease (COPD) due to tobacco smoking exhibit prolonged survival of neutrophils. Xu et al. found that human neutrophils survived longer in culture and had increased activity of the survival-signaling kinase Akt when cultured in the presence of cigarette smoke extract or nicotine. Specific pharmacological inhibitors of nicotinic acetylcholine receptors composed of α7 subunits prevented the nicotine-induced delay in neutrophil death and increase in Akt phosphorylation and partially reduced the increase in Akt phosphorylation induced by cigarette smoke extract. Pharmacological inhibition of either phosphoinositide 3-kinase (PI3K) or Akt reduced Akt phosphorylation and restored spontaneous death to the neutrophils exposed to cigarette smoke extract. Akt binding to phosphatidylinositol 3,4,5-trisphosphate (PIP3) results in recruitment of Akt to the plasma membrane, where it is activated. Using a fluorescent fusion protein, a decline in the abundance of this proxy of Akt membrane binding was observed over time in cultured mouse primary neutrophils, which was partially prevented by cigarette smoke extract or nicotine. Akt membrane recruitment is competitively blocked by either inositol(1,3,4,5)phosphate [Ins(1,3,4,5)P4] or diphosphoinositol pentakisphosphate (InsP7). Because of the short life span of neutrophils, which precluded reaching steady-state labeling, a human promyelocytic cell line, HL60, was used to measure the abundance of these lipids. Although both lipids were detected in these cells, cigarette smoke extract or nicotine reduced the abundance of only InsP7. Overexpression of InsP6 kinase 1 (InsP6K1), an enzyme that synthesizes InsP7, in HL60 cells prevented the increase in Akt activity and reduction in cell death in response to cigarette smoke extract or nicotine. Mice in which the gene encoding InsP6K1 was knocked out had reduced lung accumulation of neutrophils and of inflammatory cytokines and chemokines and reduced pulmonary edema compared with wild-type mice in response to a cigarette smoke–induced model of COPD. Thus, InsP7 functions as an inhibitor of survival Akt signaling and, by reducing its abundance, cigarette smoke enhances neutrophil accumulation and lung damage.

Y. Xu, H. Li, B. Bajrami, H. Kwak, S. Cao, P. Liu, J. Zhou, Y. Zhou, H. Zhu, K. Ye, H. R. Luo, Cigarette smoke (CS) and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate. Proc. Natl. Acad. Sci. U.S.A. 110, 7726–7731 (2013). [Abstract] [Full Text]