Cigarette smoke (CS) and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate

• Authors: Yuanfu Xu, Chinese Academy of Medical Sciences and Peking Union Medical College; Hongmei Li, Harvard University; Besnik Bajrami, Harvard University; Hyunjeong Kwak, Harvard University; Shannan Cao, Chinese Academy of Medical Sciences and Peking Union Medical College; Peng Liu, Emory University; Jiaxi Zhou, Chinese Academy of Medical Sciences and Peking Union Medical College; Yuan Zhou, Chinese Academy of Medical Sciences and Peking Union Medical College; Haiyan Zhu, Chinese Academy of Medical Sciences and Peking Union Medical College; Keqiang Ye, Emory University; Hongbo R. Luo, Harvard University
• Journal Title: Proceedings of the National Academy of Sciences
• Volume: Volume 110, Number 19
• Publisher: National Academy of Sciences | 2013-05-07, Pages 7726-7731
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1073/pnas.1302906110
• Subjects: Health Sciences, Pathology; Biology, Neuroscience
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; INOSITOL HEXAKISPHOSPHATE KINASE-2; OBSTRUCTIVE PULMONARY-DISEASE; OVARIAN-CARCINOMA CELLS; PYROPHOSPHATES; APOPTOSIS; ACTIVATION; SURVIVAL; INHIBITION; ACROLEIN; GROWTH

Abstract

Diphosphoinositol pentakisphosphate (InsP7), a higher inositol phosphate containing energetic pyrophosphate bonds, is beginning to emerge as a key cellular signaling molecule. However, the various physiological and pathological processes that involve InsP7 are not completely understood. Here we report that cigarette smoke (CS) extract and nicotine reduce InsP7 levels in aging neutrophils. This subsequently leads to suppression of Akt deactivation, a causal mediator of neutrophil spontaneous death, and delayed neutrophil death. The effect of CS extract and nicotine on neutrophil deat h can be suppressed by either directly inhibiting the PtdIns(3,4,5)P3/Akt pathway, or increasing InsP7 levels via overexpression of InsP6K1, an inositol hexakisphosphate (InsP6) kinase responsible for InsP7 production in neutrophils. Delayed neutrophil death contributes to the pathogenesis of CS-induced chronic obstructive pulmonary disease. Therefore, disruption of InsP6K1 augments CS-induced neutrophil accumulation and lung damage. Taken together, these results suggest that CS and nicotine delay neutrophil spontaneous death by suppressing InsP7 production and consequently blocking Akt deactivation in aging neutrophils. Modifying neutrophil death via this pathway provides a strategy and therapeutic target for the treatment of tobacco-induced chronic obstructive pulmonary disease.