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Lipoxin A 4 , a 5‐lipoxygenase pathway metabolite, modulates immune response during acute respiratory tularemia
Author(s) -
Singh Anju,
Rahman Tabassum,
Bartiss Rose,
Arabshahi Alireza,
Prasain Jeevan,
Barnes Stephen,
Musteata Florin Marcel,
Sellati Timothy J.
Publication year - 2017
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.4a0815-365rr
Subject(s) - tularemia , proinflammatory cytokine , biology , francisella tularensis , immunology , immune system , chemokine , pathogenesis , arachidonate 5 lipoxygenase , cytokine , phagocyte , inflammation , microbiology and biotechnology , enzyme , biochemistry , virulence , arachidonic acid , gene
Respiratory infection with Francisella tularensis ( Ft ) is characterized by a muted, acute host response, followed by sepsis‐like syndrome that results in death. Infection with Ft establishes a principally anti‐inflammatory environment that subverts host‐cell death programs to facilitate pathogen replication. Although the role of cytokines has been explored extensively, the role of eicosanoids in tularemia pathogenesis is not fully understood. Given that lipoxin A 4 (LXA 4 ) has anti‐inflammatory properties, we investigated whether this lipid mediator affects host responses manifested early during infection. The addition of exogenous LXA 4 inhibits PGE 2 release by Ft‐ infected murine monocytes in vitro and diminishes apoptotic cell death. Tularemia pathogenesis was characterized in 5‐lipoxygenase‐deficient (Alox5 −/− ) mice that are incapable of generating LXA 4 . Increased release of proinflammatory cytokines and chemokines, as well as increased apoptosis, was observed in Alox5 −/− mice as compared with their wild‐type counterparts. Alox5 −/− mice also exhibited elevated recruitment of neutrophils during the early phase of infection and increased resistance to lethal challenge. Conversely, administration of exogenous LXA 4 to Alox5 −/− mice made them more susceptible to infection thus mimicking wild‐type animals. Taken together, our results suggest that 5‐LO activity is a critical regulator of immunopathology observed during the acute phase of respiratory tularemia, regulating bacterial burden and neutrophil recruitment and production of proinflammatory modulators and increasing morbidity and mortality. These studies identify a detrimental role for the 5‐LO–derived lipid mediator LXA 4 in Ft ‐induced immunopathology. Targeting this pathway may have therapeutic benefit as an adjunct to treatment with antibiotics and conventional antimicrobial peptides, which often have limited efficacy against intracellular bacteria.