title: The interaction between IL-18 and IL-18 receptor limits the magnitude of protective immunity and enhances pathogenic responses following infection with intracellular bacteria.
abstract: The binding of IL-18 to IL-18Rα induces both proinflammatory and protective functions during infection, depending on the context in which it occurs. IL-18 is highly expressed in the liver of wild-type (WT) C57BL/6 mice following lethal infection with highly virulent Ixodes ovatus ehrlichia (IOE), an obligate intracellular bacterium that causes acute fatal toxic shock-like syndrome. In this study, we found that IOE infection of IL-18Rα(-/-) mice resulted in significantly less host cell apoptosis, decreased hepatic leukocyte recruitment, enhanced bacterial clearance, and prolonged survival compared with infected WT mice, suggesting a pathogenic role for IL-18/IL-18Rα in Ehrlichia-induced toxic shock. Although lack of IL-18R decreased the magnitude of IFN-γ producing type-1 immune response, enhanced resistance of IL-18Rα(-/-) mice against Ehrlichia correlated with increased proinflammatory cytokines at sites of infection, decreased systemic IL-10 production, increased frequency of protective NKT cells producing TNF-α and IFN-γ, and decreased frequency of pathogenic TNF-α-producing CD8(+) T cells. Adoptive transfer of immune WT CD8(+) T cells increased bacterial burden in IL-18Rα(-/-) mice following IOE infection. Furthermore, rIL-18 treatment of WT mice infected with mildly virulent Ehrlichia muris impaired bacterial clearance and enhanced liver injury. Finally, lack of IL-18R signal reduced dendritic cell maturation and their TNF-α production, suggesting that IL-18 might promote the adaptive pathogenic immune responses against Ehrlichia by influencing T cell priming functions of dendritic cells. Together, these results suggested that the presence or absence of IL-18R signals governs the pathogenic versus protective immunity in a model of Ehrlichia-induced immunopathology.
authors.affiliation: Department of Pathology, Meharry Medical College, Nashville, TN 37028, USA.
authors.forename: Purnima
authors.initials: P
authors.lastname: Ghose
authors.forename: Asim Q
authors.initials: AQ
authors.lastname: Ali
authors.forename: Rong
authors.initials: R
authors.lastname: Fang
authors.forename: Digna
authors.initials: D
authors.lastname: Forbes
authors.forename: Billy
authors.initials: B
authors.lastname: Ballard
authors.forename: Nahed
authors.initials: N
authors.lastname: Ismail
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016873:Ehrlichiosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D020382:Interleukin-18 / Q000097:blood / Q000378:metabolism*; D053727:Interleukin-18 Receptor alpha Subunit / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D007424:Intracellular Fluid / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology; D012772:Shock, Septic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha