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Acid Sphingomyelinase Amplifies Redox Signaling in Pseudomonas aeruginosa-Induced Macrophage Apoptosis¹

Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany

Recent studies indicate that distinct membrane microdomains, also named lipid rafts, and ceramide play an important role in infectious biology. Ceramide forms larger ceramide-enriched membrane platforms that are required for diverse signal transduction. In this study, we demonstrate that ceramide-enriched membrane platforms are critically involved in redox signaling that regulates alveolar macrophage apoptosis upon infection with Pseudomonas aeruginosa. In freshly isolated alveolar macrophages, P. aeruginosa infection results in rapid activation of acid sphingomyelinase (Asm), release of ceramide, and formation of ceramide-enriched membrane platforms, which are required for P. aeruginosa-induced activation of NADPH oxidase and production of reactive oxygen species (ROS). Inhibition of NADPH oxidase or removal of intracellular ROS reduced P. aeruginosa-induced activation of the Asm and formation of ceramide-enriched membrane platforms, suggesting that NADPH oxidase-derived ROS regulate Asm-initiated redox signaling in a positive feedback manner. Furthermore, stimulation of JNK and induction of apoptosis upon P. aeruginosa infections are dependent on NADPH oxidase-derived ROS. These findings indicate that ceramide-enriched membrane platforms are essential for amplification of Asm-mediated redox signaling, which mediates JNK activation and thereby apoptosis of alveolar macrophages upon P. aeruginosa infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was funded by Deutsche Forschungsgemeinschaft Grant Gu 335-16/1.

² Y.Z. and X.L. contributed equally to this work and share first authorship.

³ Address correspondence and reprint requests to Dr. Erich Gulbins, Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany. E-mail address: erich.gulbins{at}uni-due.de

⁴ Abbreviations used in this paper: CF, cystic fibrosis; Asm, acid sphingomyelinase; DAG, 1,2-diacylglycerol; DPI, diphenyleneiodonium chloride; MOI, multiplicity of infection; PFA, paraformaldehyde; PI, propidium iodide; RFU, relative fluorescence unit; ROS, reactive oxygen species; Smpd1^–/–, sphingomyelin phosphodiesterase 1 knockout; WT, wild type; H₂DCFDA, 2',7'-dichlorodihydrofluorescein diacetate.