Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6.
Innate immune signaling is critical for the development of protective immunity. Such signaling is, perforce, tightly controlled. Lipoxins (LXs) are eicosanoid mediators that play key counterregulatory roles during infection. The molecular mechanisms underlying LX-mediated control of innate immune signaling are of interest. In this study, we show that LX and aspirin (ASA)-triggered LX (ATL) inhibit innate immune signaling by inducing suppressor of cytokine signaling (SOCS) 2-dependent ubiquitinylation and proteasome-mediated degradation of TNF receptor-associated factor (TRAF) 2 and TRAF6, which are adaptor molecules that couple TNF and interleukin-1 receptor/Toll-like receptor family members to intracellular signaling events. LX-mediated degradation of TRAF6 inhibits proinflammatory cytokine production by dendritic cells. This restraint of innate immune signaling can be ablated by inhibition of proteasome function. In vivo, this leads to dysregulated immune responses, accompanied by increased mortality during infection. Proteasomal degradation of TRAF6 is a central mechanism underlying LX-driven immune counterregulation, and a hitherto unappreciated mechanism of action of ASA. These findings suggest a new molecular target for drug development for diseases marked by dysregulated inflammatory responses.
Machado
Fabiana S
FS
Divisions of Molecular Immunology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Esper
Lísia
L
Dias
Alexandra
A
Madan
Rajat
R
Gu
YuanYuan
Y
Hildeman
David
D
Serhan
Charles N
CN
Karp
Christopher L
CL
Aliberti
Júlio
J
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001921:Brain / Q000276:immunology / Q000503:physiopathology; D002467:Cell Nucleus / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D016753:Interleukin-10 / Q000172:deficiency; D044045:Lipoxins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D013154:Spleen / Q000276:immunology / Q000503:physiopathology; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D044045:Lipoxins; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D052247:Nitric Oxide Synthase Type II; D046988:Proteasome Endopeptidase Complex; D001241:Aspirin