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 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 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.

The Required Role of Endogenously Produced Lipoxin A4 and Annexin-1 for the Production of IL-10 and Inflammatory Hyporesponsiveness in Mice

“…In the latter study, lipoxins were not found to induce IL-10 production and the actions of IL-10 in the system differed from those of lipoxins (13). Moreover, in a model of renal ischemia reperfusion injury in vivo, mice treated with the same analog used in this work displayed increased mRNA levels for SOCS-1 and SOCS-2 (42).…”

“…It has been recently reported that SOCS-2 is a critical intracellular regulator of the immunoregulatory and anti-inflammatory actions of lipoxins in mice infected with the intracellular parasite Toxoplasma gondii (13). In the latter study, lipoxins were not found to induce IL-10 production and the actions of IL-10 in the system differed from those of lipoxins (13).…”

“…There has been much recent interest in a series of mediators of the inflammatory process which possess significant antiinflammatory actions when given exogenously, including lipoxin A 4 (LXA 4 ) 3 and annexin-1 (ANXA-1, previously referred to as lipocortin-1) (9 -12). The mechanisms by which these molecules modulate the inflammatory response are not clearly shown and a recent study suggested that control of SOCS-2 activation might be relevant for the action of LXA 4 under certain conditions (13). It has been demonstrated that activation of the LXA 4 receptor downregulates polymorphonuclear (PMN) responses in vitro and promotes resolution of inflammation through up-regulation of NAB1, a transcriptional corepressor identified previously as a glucocorticoid-responsive gene (14).…”

Characterization of Quin-C1 for its anti-inflammatory property in a mouse model of bleomycin-induced lung injury

“…Thus, it is necessary to further determine the dose-response characteristics of these ligands at the level of receptors and receptor-mediated signaling pathways. Finally, the FPR2/ALX-mediated agonistic activities of selected ligands appear to be indispensable for inducing anti-inflammatory proteins such as suppressor of cytokine signaling 2 (SOCS-2) as well as enhancing the proresolving functions of macrophages [42,43] . Consistent with these findings, FPR2/ALX has been shown to mediate different functions of LXA4 in neutrophils and macrophages [44] .…”

Toxoplasmosis, Pancreatitis, Obesity and Drug Discovery

“…Sera levels of lipoxin A4 rise during infection and remain high in chronic infection but lack of lipoxin A4 increases mortality following infection which may be cytokine mediated tissue injury [23,24]. Additionally, Toxoplasma lacks the ability to synthesize sterol for growth and replication and depends on the host blood cholesterol by scavenging the low-density lipoprotein receptors.…”