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

• Type of Material: Article
• 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
• Language: English
• Date: 2013-05-07
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2013 National Academy of Sciences.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1302906110
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 110
• Issue: 19
• Start Page: 7726
• End Page: 7731
• Grant/Funding Information: Y.X. is supported by National Basic Research Program of China (2012CB966403), Chinese National Natural Science Foundation (31271484 and 81170512), and Tianjin Natural Science Foundation (12JCZDJC24600).; H.R.L. is supported by National Institutes of Health Grants HL085100, AI076471, and HL092020.
• Keywords: APOPTOSIS; GROWTH; Science & Technology - Other Topics; ACTIVATION; OVARIAN-CARCINOMA CELLS; Science & Technology; PYROPHOSPHATES; Multidisciplinary Sciences; SURVIVAL; INOSITOL HEXAKISPHOSPHATE KINASE-2; OBSTRUCTIVE PULMONARY-DISEASE; INHIBITION; ACROLEIN
• Research Categories: Biology, Neuroscience; Health Sciences, Pathology

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.