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 pro-inflammatory 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 to infected WT mice, suggesting a pathogenic role of IL-18/IL-18Rα in Ehrlichia-induced toxic shock. Although lack of IL-18R decreases the magnitude of IFN-γ producing type-1 immune response, enhanced resistance of the IL-18Rα-/- mice against Ehrlichia correlated with increased pro-inflammatory cytokines at sites of infection, decreased systemic IL-10 production, increased frequency of protective natural killer T (NKT) cells producing TNF-α and IFN-γ and decreased frequency of pathogenic TNF-α-producing CD8+ T cells. Adoptive transfer of immune wild type 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 (EM) impaired bacterial clearance and enhanced liver injury. Finally, lack of IL-18R signal reduced dendritic cells (DCs) maturation and their TNF-α production, suggesting that IL-18 possibly promote the adaptive pathogenic immune responses against Ehrlichia via influencing T cell priming functions of DCs Together, these results suggest that the presence or absence of IL-18R signals governs the pathogenic versus protective immunity in a model of Ehrlichia-induced immunopathology.

The adaptor ASC exacerbates lethal Listeria monocytogenes infection by mediating IL‐18 production in an inflammasome‐dependent and ‐independent manner

“…Alternatively, PR3 might induce the secretion of mature IL-18 by activating protease-activated receptor 2 [47]. In a series of studies, IL-18R and NK cells have been shown to play a pathologic role in lethal systemic infection with Ixodes ovatus ehrlichia, a Gram-negative obligate intracellular bacterium [33,48]. The studies have shown that either IL-18R deficiency or depletion of NK cells leads to higher resistance to this pathogen, reduced liver injury, and lower IL-10 production as compared to controls.…”

Experimental infection of chickens by a flagellated motile strain of Salmonella enterica serovar Gallinarum biovar Gallinarum

“…At this time point, chicks infected with SG had clinical signs of FT and more severe histopathological changes than those infected with SG Fla + , suggesting that IL-18 over-expression could be related to the severity of disease. IL-18 promotes inflammation and enhances CD8 + T lymphocyte proliferation and cytotoxic activity (Eckmann and Kagnoff, 2001;Raupach et al, 2006;Ghose et al, 2011).…”

Neutrophils Mediate Immunopathology and Negatively Regulate Protective Immune Responses during Fatal Bacterial Infection-Induced Toxic Shock

“…However, failure to remove apoptotic neutrophils resulted in sustained inflammation (23)(24)(25)(26). Studies have demonstrated that elevated levels of Ccr1 during bacterial peritonitis and sepsis were associated with neutrophil accumulation and severe pathology while Ccr1 deficiency decreased neutrophil accumulation and abrogated inflammation and pathology in a murine model of kidney injury and inflammation (27), suggesting that neutrophils play a pathogenic role in sepsis.…”

“…Our previous study indicated that NKT cells play a dual role during lethal Ehrlichia infection. While IFN-␥ production by NKT cells is essential for effective intracellular bacterial clearance, they also promote infection-induced toxic shock syndrome (27,30,31). In contrast, NK cells play a detrimental role during fatal ehrlichiosis as they inhibit protective anti-Ehrlichia immunity and mediate tissue injury during fatal disease (29,31,32).…”