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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 vivo. In the absence of LXA₄ biosynthetic pathways, the resulting uncontrolled inflammation during infection is lethal, despite pathogen clearance. 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 …