title: Lipoxin A₄ and 15-epi-lipoxin A₄ protect against experimental cerebral malaria by inhibiting IL-12/IFN-γ in the brain.
abstract: Cerebral malaria is caused by infection with Plasmodium falciparum and can lead to severe neurological manifestations and predominantly affects sub-Saharan African children. The pathogenesis of this disease involves unbalanced over-production of pro-inflammatory cytokines. It is clear that signaling though IL-12 receptor is a critical step for development of cerebral malaria, IL-12 genetic deficiency failed to show the same effect, suggesting that there is redundancy among the soluble mediators which leads to immunopathology and death. Consequently, counter-regulatory mediators might protect the host during cerebral malaria. We have previously showed that endogenously produced lipoxins, which are anti-inflammatory mediators generated by 5-lipoxygenase (5-LO)-dependent metabolism of arachidonic acid, limit host damage in a model of mouse toxoplasmosis. We postulated here that lipoxins might also play a counter-regulatory role during cerebral malaria. To test this hypothesis, we infected 5-LO-deficient hosts with P. berghei ANKA strain, which induces a mouse model of cerebral malaria (ECM). Our results show accelerated mortality concomitant with exuberant IL-12 and IFN-γ production in the absence of 5-lipoxygenase. Moreover, in vivo administration of lipoxin to 5-LO-deficient hosts prevented early mortality and reduced the accumulation of CD8(+)IFN-γ (+) cells in the brain. Surprisingly, WT animals treated with lipoxin either at the time of infection or 3 days post-inoculum also showed prolonged survival and diminished brain inflammation, indicating that although protective, endogenous lipoxin production is not sufficient to optimally protect the host from brain damage in cerebral malaria. These observations establish 5-LO/LXA4 as a host protective pathway and suggest a new therapeutic approach against human cerebral malaria (HCM). (255 words).
authors.affiliation: Divisions of Cellular and Molecular Immunology and Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati, College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Shryock
authors.forename: Cortez
authors.initials: C
authors.lastname: McBerry
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Salazar Gonzalez
authors.forename: Steven
authors.initials: S
authors.lastname: Janes
authors.forename: Fabio T M
authors.initials: FT
authors.lastname: Costa
authors.forename: Julio
authors.initials: J
authors.lastname: Aliberti
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D044045:Lipoxins / Q000627:therapeutic use*; D016779:Malaria, Cerebral / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D010962:Plasmodium berghei / Q000472:pathogenicity
chemical_list: D044045:Lipoxins; C040527:lipoxin A4; D018664:Interleukin-12; D007371:Interferon-gamma; D001094:Arachidonate 5-Lipoxygenase