Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 45, Pages 32563-32573Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.483750
Keywords
Autophagy; Ceramide; Inflammation; Lysosomes; Macrophages; Sphingolipid; Sphingosine 1-Phosphate
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Funding
- National Institutes of Health [HL67330, HL70694, HL89934]
- INSERM Avenir
- Marie Curie Actions
- French National Research Agency
- Fondation de France
- Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313]
- Lipidomics Core in the South Carolina Lipidomics and Pathobiology COBRE [P20 RR017677]
- NIDDK, National Institutes of Health
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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 NFB 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 (M phi Sphk dKO). Compared with WT counterparts, M phi 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 M phi Sphk dKO cells compared with WT counterparts. Treatment of WT and M phi Sphk dKO with inflammatory mediators TNF or Escherichia coli LPS resulted in similar NFB activation and cytokine expression. Furthermore, LPS-induced inflammatory responses, mortality, and thioglycolate-induced macrophage recruitment to the peritoneum were indistinguishable between M phi 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.
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