An Obligate Role for Membrane-Associated Neutral Sphingomyelinase Activity in Orienting Chemotactic Migration of Human Neutrophils

Sitrin, Robert G.; Sassanella, Timothy M.; Petty, Howard R.

doi:10.1165/rcmb.2010-0019oc

Cited by 25 publications

(28 citation statements)

References 50 publications

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“…Polymorphonuclear cells, of which the phagocytic neutrophils constitute the major portion, display a plasma membrane NSMase activity that increases during phagocytosis (Hinkovska-Galcheva et al , 1998). Inhibition of nSMase2 by GW4869 causes loss of directional motility and migration in these cells (Sitrin et al , 2011). Finally, peptidoglycan, a major component of bacterial cell wall, was shown to induce nSMase2 activity in human macrophages that leads to the activation of p38 MAPK and NF-κB to increase cyclooxygenase-2 expression (Chen et al , 2009).…”

Section: Nsmase2 As a Regulator Of Biological Functionsmentioning

confidence: 99%

Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes

Shamseddine

Airola²,

Hannun³

2015

Advances in Biological Regulation

178

161

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Our understanding of the functions of ceramide signaling has advanced tremendously over the past decade. In this review, we focus on the roles and regulation of neutral sphingomyelinase 2 (nSMase2), an enzyme that generates the bioactive lipid ceramide through the hydrolysis of the membrane lipid sphingomyelin. A large body of work has now implicated nSMase2 in a diverse set of cellular functions, physiological processes, and disease pathologies. We discuss different aspects of this enzyme’s regulation from transcriptional, post-translational, and biochemical. Furthermore, we highlight nSMase2 involvement in cellular processes including inflammatory signaling, exosome generation, cell growth, and apoptosis, which in turn play important roles in pathologies such as cancer metastasis, Alzheimer’s disease, and other organ systems disorders. Lastly, we examine avenues where targeted nSMase2-inhibition may be clinically beneficial in disease scenarios.

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Section: Nsmase2 As a Regulator Of Biological Functionsmentioning

confidence: 99%

Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes

Shamseddine

Airola²,

Hannun³

2015

Advances in Biological Regulation

178

161

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“…Additionally, neutrophil expression of LPA 1 and S1P 3 were dramatically increased in neutrophils isolated from peripheral blood of patients with pneumonia, and were more responsive to chemotactic stimuli than those from healthy subjects 173 . These differences are intriguing in light of the recent study demonstrating that neutral sphingomyelinase, a modulator upstream of S1P synthesis, polarizes the distribution of Rac1/2 versus RhoA at the leading edge of elongated neutrophils 175 . Additional evidence of the effect of S1PR on neutrophil migration was demonstrated in studies using Sgpl-/- mice 176 : S1P lyase deficiency increased neutrophil numbers in circulation by impairing homeostatic chemotaxis into tissues.…”

Section: Immune Systemmentioning

confidence: 99%

Regulation of Mammalian Physiology, Development, and Disease by the Sphingosine 1-Phosphate and Lysophosphatidic Acid Receptors

2011

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“…nSMase activity and ceramide levels have been shown to be increased in aged endothelial tissue having decreased vessel relaxation, which was reversible by nSMase inhibition with GW4869 (Smith et al ., 2006). It has also been used to demonstrate involvement of nSMase2 in hypoxic pulmonary vasoconstriction and chemotaxis of neutrophils (Cogolludo et al ., 2009; Sitrin et al ., 2010). A role for nSMase2 in various neurological processes, including synaptic plasticity (Wheeler et al ., 2009) and spatial memory (Tabatadze et al ., 2010) have been suggested based on results with GW4869.…”

Section: Sphingomyelinasesmentioning

confidence: 99%

Drug targeting of sphingolipid metabolism: sphingomyelinases and ceramidases

Canals

Perry

Jenkins

et al. 2011

British J Pharmacology

153

115

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Sphingolipids represent a class of diverse bioactive lipid molecules that are increasingly appreciated as key modulators of diverse physiologic and pathophysiologic processes that include cell growth, cell death, autophagy, angiogenesis, and stress and inflammatory responses. Sphingomyelinases and ceramidases are key enzymes of sphingolipid metabolism that regulate the formation and degradation of ceramide, one of the most intensely studied classes of sphingolipids. Improved understanding of these enzymes that control not only the levels of ceramide but also the complex interconversion of sphingolipid metabolites has provided the foundation for the functional analysis of the roles of sphingolipids. Our current understanding of the roles of various sphingolipids in the regulation of different cellular processes has come from loss-of-function/gain-of-function studies utilizing genetic deletion/downregulation/overexpression of enzymes of sphingolipid metabolism (e.g. knockout animals, RNA interference) and from the use of pharmacologic inhibitors of these same enzymes. While genetic approaches to evaluate the functional roles of sphingolipid enzymes have been instrumental in advancing the field, the use of pharmacologic inhibitors has been equally important in identifying new roles for sphingolipids in important cellular processes.The latter also promises the development of novel therapeutic targets with implications for cancer therapy, inflammation, diabetes, and neurodegeneration. In this review, we focus on the status and use of pharmacologic compounds that inhibit sphingomyelinases and ceramidases, and we will review the history, current uses and future directions for various small molecule inhibitors, and will highlight studies in which inhibitors of sphingolipid metabolizing enzymes have been used to effectively treat models of human disease.

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An Obligate Role for Membrane-Associated Neutral Sphingomyelinase Activity in Orienting Chemotactic Migration of Human Neutrophils

Cited by 25 publications

References 50 publications

Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes

Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes

Regulation of Mammalian Physiology, Development, and Disease by the Sphingosine 1-Phosphate and Lysophosphatidic Acid Receptors

Drug targeting of sphingolipid metabolism: sphingomyelinases and ceramidases

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