Parasite-induced lipoxin A4 is an endogenous regulator of IL-12 production and immunopathology in Toxoplasma gondii infection.
The production of interleukin (IL)-12 is critical for the development of interferon (IFN)-gamma-dependent resistance to Toxoplasma gondii. Nevertheless, when this response is dysregulated, such as occurs in the absence of IL-10, the uncontrolled inflammation that results can have lethal consequences for the host. Recently, we demonstrated that lipoxin (LX)A(4), an eicosanoid mediator that depends on 5-lipoxygenase (LO) for its biosynthesis, exerts a regulatory role on dendritic cell IL-12 production triggered artificially by a T. gondii extract. We now formally establish the physiological relevance of this pathway in the systemic control of IL-12 production induced by live T. gondii infection and demonstrate its function to be distinct from that of IL-10. Thus, T. gondii-exposed wild-type, but not 5-LO-deficient animals, produced high levels of serum LXA(4) beginning at the onset of chronic infection. Moreover, 5-LO(-/-), in contrast to wild-type mice, succumbed during the same period displaying a marked encephalitis. The increased mortality of the 5-LO(-/-) animals was also associated with significant elevations of IL-12 and IFN-gamma and was completely prevented by the administration of a stable LXA(4) analogue. Together, these findings demonstrate a new pathway involving the induction of host LXs for the in vivo regulation of proinflammatory responses during microbial infection.
Aliberti
Julio
J
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA. jaliberti@niaid.nih.gov
Serhan
Charles
C
Sher
Alan
A
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000276:immunology*; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D006893:Hydroxyeicosatetraenoic Acids / Q000008:administration & dosage / Q000097:blood / Q000276:immunology*; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D044045:Lipoxins; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014122:Toxoplasma / Q000276:immunology; D014123:Toxoplasmosis / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D006893:Hydroxyeicosatetraenoic Acids; D044045:Lipoxins; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D001094:Arachidonate 5-Lipoxygenase