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Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent

Abstract

Control of inflammation is crucial to prevent damage to the host during infection. Lipoxins and aspirin-triggered lipoxins are crucial modulators of proinflammatory responses; however, their intracellular mechanisms have not been completely elucidated. We previously showed that lipoxin A4 (LXA4) controls migration of dendritic cells (DCs) and production of interleukin (IL)-12 in vivo1. In the absence of LXA4 biosynthetic pathways, the resulting uncontrolled inflammation during infection is lethal, despite pathogen clearance2. Here we show that lipoxins activate two receptors in DCs, AhR and LXAR, and that this activation triggers expression of suppressor of cytokine signaling (SOCS)-2. SOCS-2–deficient DCs are hyper-responsive to microbial stimuli, as well as refractory to the inhibitory actions of LXA4, but not to IL-10. Upon infection with an intracellular pathogen, SOCS-2–deficient mice had uncontrolled production of proinflammatory cytokines, decreased microbial proliferation, aberrant leukocyte infiltration and elevated mortality. We also show that SOCS-2 is a crucial intracellular mediator of the anti-inflammatory actions of aspirin-induced lipoxins in vivo.

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Figure 1: LXA4 induces expression of Socs2 in vitro and in vivo.
Figure 2: SOCS-2 and AhR are required for LXA4-dependent inhibition of IL-12 in vitro and in vivo.
Figure 3: Increased inflammation and mortality of SOCS-2–deficient mice during T. gondii infection. Wild-type (white bars) or SOCS-2–deficient (black bars) mice were injected intraperitoneally with 20 cysts of T. gondii (ME49 strain).
Figure 4: SOCS-2 is required for endogenous lipoxin and aspirin-triggered anti-inflammatory actions in vivo.

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Acknowledgements

We acknowledge reading and suggestions from A. Sher, S. Abraham and R. Corn. We also thank H. Tanowitz and L. Weiss for histopathological analysis of T. gondii–infected SOCS-2−deficient mice and W. Alexander for providing SOCS-2−deficient mice. C.N.S. is funded by National Institutes of Health grants GM38765 and P50-DE0161912.

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Correspondence to Fabiana S Machado or Julio Aliberti.

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Supplementary information

Supplementary Fig. 1

IL-10-dependent induction of SOCS-1 and SOCS-3 in DCs and AhR- and 5-LO–independent induction of SOCS-2 in vivo. (PDF 141 kb)

Supplementary Fig. 2

Higher serum levels of IL-12 and IFN-γ in T. gondii–infected SOCS-2–deficient mice. (PDF 67 kb)

Supplementary Fig. 3

SOCS-2 induction correlates with aberrant proinflammatory responses during acute and chronic toxoplasmosis in SOCS-2–deficient mice. (PDF 183 kb)

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Machado, F., Johndrow, J., Esper, L. et al. Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent. Nat Med 12, 330–334 (2006). https://doi.org/10.1038/nm1355

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