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Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity

Abstract

Lipoxins are eicosanoid mediators that show potent inhibitory effects on the acute inflammatory process. We show here that the induction of lipoxin A4 (LXA4) accompanied the in vivo suppression of interleukin 12 (IL-12) responsiveness of murine splenic dendritic cells (DCs) after microbial stimulation with an extract of Toxoplasma gondii. This paralysis of DC function could not be triggered in mice that were deficient in a key lipoxygenase involved in LXA4 biosynthesis. In addition, DCs pre-treated with LXA4 became refractory to microbial stimulation for IL-12 production in vitro and mice injected with a stable LXA4 analog showed reduced splenic DC mobilization and IL-12 responses in vivo. Together, these findings indicate that the induction of lipoxins in response to microbial stimulation can provide a potent mechanism for regulating DC function during the innate response to pathogens.

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Figure 1: T. gondii stimulates lipoxin production in vivo.
Figure 2: Induction of 5-LO in murine spleen and in a CD11cCD11bhi splenic subpopulation after STAg injection.
Figure 3: 5-LO–deficient mice do not develop STAg-induced paralysis of DC function.
Figure 4: Splenic DCs from 5-LO–deficient animals do not sustain CCR5 down-regulation after STAg injection.
Figure 5: LXA4 inhibits STAg-, but not LPS-, induced IL-12 production by purified CD11c+ splenic DCs.
Figure 6: Mice injected with the LXA4 stable analog show impaired DC mobilization and IL-12 production when challenged with STAg.

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Acknowledgements

We thank P. Murphy and B. Kelsall for their comments on this manuscript as well as C. Clish, S. Huong, J. Brannon and G. Mirick for their invaluable assistance with the eicosanoid analysis. Supported in part by National Institutes of Health grants GM-38765 and PO1-DE13499 (to C. N. S.).

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Correspondence to J. Aliberti.

Supplementary information

Web Figure 1.

MS-MS of endogenous LTB4 generated in vivo after STAg injection. A representative MS-MS from individual murine spleens (n=8) collected 6 h after STAg injection. The diagnostic ions and relative intensity matched those obtained with the authentic eicosanoids indicated for the LC-MS acquisition conditions. (GIF 17 kb)

Web Figure 2.

MS-MS of endogenous 15(S)-HETE generated in vivo after STAg injection. A representative MS-MS from individual murine spleens (n=8) collected 6 h after STAg injection. The diagnostic ions and relative intensity matched those obtained with the authentic eicosanoids indicated for the LC-MS acquisition conditions. (GIF 16 kb)

Web Figure 3.

MS-MS of endogenous 12(S)-HETE generated in vivo after STAg injection. A representative MS-MS from individual murine spleens (n=8) collected 6 h after STAg injection. The diagnostic ions and relative intensity matched those obtained with the authentic eicosanoids indicated for the LC-MS acquisition conditions. (GIF 21 kb)

Web Figure 4.

MS-MS of endogenous 5(S)-HETE generated in vivo after STAg injection. A representative MS-MS from individual murine spleens (n=8) collected 6 h after STAg injection. The diagnostic ions and relative intensity matched those obtained with the authentic eicosanoids indicated for the LC-MS acquisition conditions. (GIF 15 kb)

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Aliberti, J., Hieny, S., Reis e Sousa, C. et al. Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity. Nat Immunol 3, 76–82 (2002). https://doi.org/10.1038/ni745

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