Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections

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Abstract

Endogenous mechanisms leading to host protection and resolution of infections without immunosuppression are of wide interest1,2. Here we elucidate the structures of four new host-protective molecules produced in neutrophil-endothelial cocultures and present in human and mouse tissues after sterile inflammation or infection. The bioactive molecules contain conjugated triene and diene double bonds, carry an alcohol at C13 and are derived from n-3 docosapentaenoic acid (DPA, C22:5). These compounds, termed 13-series resolvins (RvTs), demonstrated potent protective actions increasing mice survival during Escherichia coli infections. RvTs also regulated human and mouse phagocyte responses stimulating bacterial phagocytosis and regulating inflammasome components. Their biosynthesis during neutrophil-endothelial cell interactions was initiated by endothelial cyclooxygenase-2 (COX-2), increased by atorvastatin via S-nitrosylation of COX-2 and reduced by COX-2 inhibitors. The actions of atorvastatin and RvTs were additive in E. coli infections in mice, where they accelerated resolution of inflammation and increased survival >60%. Taken together, these results document host-protective molecules in bacterial infections, namely RvTs, derived from n-3 DPA via transcellular biosynthesis and increased by atorvastatin. These molecules regulate key innate protective responses in the resolution of infectious inflammation.

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Figure 1: RvTs from neutrophil-endothelial cell interactions are elevated in self-resolving inflammation.
Figure 2: Atorvastatin increases protective actions of neutrophil-endothelial cell fractions during mouse infections and promotes RvT formation via S-nitrosylated COX-2.
Figure 3: RvT regulate leukocyte responses and promote survival in infections.
Figure 4: Atorvastatin and RvT accelerate resolution of infections and promote survival in bacterial infections in mice.

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Acknowledgements

The authors thank R. Colas and I. Vlasakov for assistance with material preparation and lipid mediator metabololipidomics. This work was supported by the National Institutes of Health (P01GM095467 to C.N.S.).

Author information

J.D. and N.C. designed and carried out experiments and analyzed data; J.D. and C.N.S. conceived the overall research plan and experimental design. All authors contributed to manuscript and figure preparation.

Correspondence to Charles N Serhan.

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The authors declare no competing financial interests.

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Supplementary Figures 1–10 and Supplementary Tables 1–6 (PDF 3270 kb)

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Dalli, J., Chiang, N. & Serhan, C. Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections. Nat Med 21, 1071–1075 (2015) doi:10.1038/nm.3911

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