Year: 2013
Type: article
Abstract: Sphingosine kinases (Sphks), which catalyze the formation of sphingosine 1-phosphate (S1P) from sphingosine, have been implicated as essential intracellular messengers in inflammatory responses. Specifically, intracellular Sphk1-derived S1P was reported to be required for NFκB induction during inflammatory cytokine action. To examine the role of intracellular S1P in the inflammatory response of innate immune cells, we derived murine macrophages that lack both Sphk1 and Sphk2 (MΦ Sphk dKO). Compared with WT counterparts, MΦ Sphk dKO cells showed marked suppression of intracellular S1P levels whereas sphingosine and ceramide levels were strongly up-regulated. Cellular proliferation and apoptosis were similar in MΦ Sphk dKO cells compared with WT counterparts. Treatment of WT and MΦ Sphk dKO with inflammatory mediators TNFα or Escherichia coli LPS resulted in similar NFκB activation and cytokine expression. Furthermore, LPS-induced inflammatory responses, mortality, and thioglycolate-induced macrophage recruitment to the peritoneum were indistinguishable between MΦ Sphk dKO and littermate control mice. Interestingly, autophagic markers were constitutively induced in bone marrow-derived macrophages from Sphk dKO mice. Treatment with exogenous sphingosine further enhanced intracellular sphingolipid levels and autophagosomes. Inhibition of autophagy resulted in caspase-dependent cell death. Together, these data suggest that attenuation of Sphk activity, particularly Sphk2, leads to increased intracellular sphingolipids and autophagy in macrophages. Background: Sphingosine kinases (Sphks) were proposed to be essential for inflammatory responses. Results: Robust inflammatory responses were seen in macrophages that lack Sphks. However, intracellular sphingolipids and autophagic vesicles were induced. Conclusion: Sphingosine kinases are not required for inflammation. Significance: Attenuation of Sphk activity may not be critical for inflammation but could lead to altered sphingolipid levels and autophagy.
Source: Journal of Biological Chemistry
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Funders: University of South Carolina, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation de France, National Institutes of Health, Hollings Cancer Center, Medical University of South Carolina, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources
Awards: G1410469566, COBRE in Lipidomics and Pathobiology, Sphingolipid modulators of vascular growth &homeostasis, Sphingolipid modulators of vascular growth & homeostasis, G4154007543, Sphingosine 1-phosphate receptors in vascular homeostasis and pathology, G4796340452, Interactive Signaling Modules in Vascular Inflammation, G7998839784, G9000100095, G9000204985, G9000236996, Medical University of South Carolina - Cancer Center Support Grant, G943025626
OpenAlex ID: W2011345944