Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent.
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.
Machado
Fabiana S
FS
Department of Immunology, Duke University Medical Center, Durham, North Carolina 27705, USA.
Johndrow
James E
JE
Esper
Lisia
L
Dias
Alexandra
A
Bafica
Andre
A
Serhan
Charles N
CN
Aliberti
Julio
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins; D001921:Brain / Q000166:cytology / Q000469:parasitology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors; D044045:Lipoxins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014122:Toxoplasma / Q000472:pathogenicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D051792:Basic Helix-Loop-Helix Proteins; D018664:Interleukin-12; D044045:Lipoxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D050826:Suppressor of Cytokine Signaling Proteins; C484722:Ahr protein, mouse; C491409:Socs2 protein, mouse; C040527:lipoxin A4