Attenuation of Intestinal Inflammation in Interleukin-10-Deficient Mice Infected with Citrobacter rodentium

Abstract

dInterleukin-10 (IL-10) curtails immune responses to microbial infection and autoantigens and contributes to intestinal immune homeostasis, yet administration of IL-10 has not been effective at attenuating chronic intestinal inflammatory conditions, suggesting that its immune functions may be context dependent. To gain a broader understanding of the importance of IL-10 in controlling mucosal immune responses to infectious challenges, we employed the murine attaching and effacing pathogen Citrobacter rodentium, which colonizes primarily the surfaces of the cecum and colon and causes transient mucosal inflammation driven by Th17 and Th1 T helper cells. Infection induced macrophage and dendritic cell production of IL-10, which diminished antibacterial host defenses, because IL-10-deficient mice cleared infection faster than wild-type controls. In parallel, the mice had less acute infection-associated colitis and resolved it more rapidly than controls. Importantly, transient C. rodentium infection protected IL-10-deficient mice against the later development of spontaneous colitis that normally occurs with aging in these mice. Genome-wide expression studies revealed that IL-10 deficiency was associated with downregulation of proinflammatory pathways but increased expression of the anti-inflammatory cytokine IL-27 in response to infection. IL-27 was found to suppress in vitro Th17 and, to a lesser degree, Th1 differentiation independent of IL-10. Furthermore, neutralization of IL-27 resulted in more severe colitis in infected IL-10-deficient mice. Together, these findings indicate that IL-10 is dispensable for resolving C. rodentium-associated colitis and further suggest that IL-27 may be a critical factor for controlling intestinal inflammation and Th17 and Th1 development by IL-10-independent mechanisms.

The Immunobiology of Interleukin-27

“…Together with a recent report that the IL-27Rα chain can be shed and that serum levels of sIL-27Rα were elevated in patients with CD (64), it is possible that IL-27p28 or sIL-27Rα may be useful as biomarkers for disease progression. It should be noted that the bacterium Citrobacter rodentium had the ability to induce inflammation in mice deficient in IL-10, but this effect was ameliorated by IL-27 (206). This finding provides evidence that, in addition to its ability to induce IL-10, IL-27 has other suppressive effects in the gut, further strengthening the rationale for using IL-27 to treat these conditions.…”

Interleukin-27 as a Novel Therapy for Inflammatory Bowel Disease

“…Antibody neutralization of IL-27 in mice infected with Citrobacter rodentium precipitated more severe colitis and increased production of IL-6. 43 In another study, a more proinflammatory phenotype was observed in regulatory T cells lacking IL-27Rα, which produced more IL-17 and less IL-10 than regulatory T cells from wild type mice. 45 The consequences of this altered phenotype due to IL-27Rα deletion were reported by another laboratory using the T cell transfer model of enterocolitis.…”

“…43–47 Mucosal administration of IL-27 synthesized in situ by a food-grade bacterium improved survival and significantly decreased disease activity, colon and small intestine histopathology scores, and proinflammatory gene expression within the intestine in a mouse model of enterocolitis induced by T cell transfer. 44 The treatment effects in this study were both T cell- and IL-10-dependent; however, mucosal delivery of IL-27 was found to be more efficacious than direct mucosal delivery of IL-10 by the bacteria.…”

<i>Citrobacter rodentium</i>, a Gut Pathogen: The Yin and the Yang of Its Pathophysiology, Immunity and Clinical Manifestation in Mice

“…Alternatively, IL-12 deficient mice had been shown to elicit higher bacterial numbers for the first 3 weeks of infection and eventually cleared infection by day 35 [30]. found dispensable in controlling inflammation as IL-10 ablated mice resolved infection earlier than wild-type mice and had less infection associated colitis [72]. In addition, following infection, IL-27 was produced which subsequently suppressed Th17 in vitro and thus play role in anti-inflammatory circuit in the absence of IL-10.…”