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IL-27 Signaling Is Crucial for Survival of Mice Infected with African Trypanosomes via Preventing Lethal Effects of CD4+ T Cells and IFN-γ.

Liu G, Xu J, Wu H, Sun D, Zhang X, Zhu X, Magez S, Shi M - PLoS Pathog. (2015)

Bottom Line: This coincides with the development of an exacerbated Th1-mediated immune response with overactivation of CD4+ T cells and strongly enhanced production of inflammatory cytokines including IFN-γ.Thus, our data identify IL-27 signaling as a novel pathway to prevent early mortality via inhibiting hyperactivation of CD4+ Th1 cells and their excessive secretion of IFN-γ during infection with African trypanosomes.These data are the first to demonstrate the essential role of IL-27 signaling in regulating immune responses to extracellular protozoan infections.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America.

ABSTRACT
African trypanosomes are extracellular protozoan parasites causing a chronic debilitating disease associated with a persistent inflammatory response. Maintaining the balance of the inflammatory response via downregulation of activation of M1-type myeloid cells was previously shown to be crucial to allow prolonged survival. Here we demonstrate that infection with African trypanosomes of IL-27 receptor-deficient (IL-27R-/-) mice results in severe liver immunopathology and dramatically reduced survival as compared to wild-type mice. This coincides with the development of an exacerbated Th1-mediated immune response with overactivation of CD4+ T cells and strongly enhanced production of inflammatory cytokines including IFN-γ. What is important is that IL-10 production was not impaired in infected IL-27R-/- mice. Depletion of CD4+ T cells in infected IL-27R-/- mice resulted in a dramatically reduced production of IFN-γ, preventing the early mortality of infected IL-27R-/- mice. This was accompanied by a significantly reduced inflammatory response and a major amelioration of liver pathology. These results could be mimicked by treating IL-27R-/- mice with a neutralizing anti-IFN-γ antibody. Thus, our data identify IL-27 signaling as a novel pathway to prevent early mortality via inhibiting hyperactivation of CD4+ Th1 cells and their excessive secretion of IFN-γ during infection with African trypanosomes. These data are the first to demonstrate the essential role of IL-27 signaling in regulating immune responses to extracellular protozoan infections.

No MeSH data available.


Related in: MedlinePlus

IL-10 production is not impaired in IL-27R-/- (WSX-1-/-) mice infected with T. congolense.(A) Parasitemia and survival of IL-27R-/- and wild-type mice (n = 4–10) treated with 0.4 mg anti-IL-10R mAb or rat IgG on day 0, 2, 4, and 6 after infection with T. congolense, respectively. (B) IL-10 levels in plasma, and supernatant fluids of cultured spleen cells, and liver leukocytes from IL-27R-/- and wild-type mice (n = 4) on day 7 and 10 after infection with T. congolense. Data are presented as the mean ± SEM. The results presented are representative of 2–3 separate experiments.
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ppat.1005065.g004: IL-10 production is not impaired in IL-27R-/- (WSX-1-/-) mice infected with T. congolense.(A) Parasitemia and survival of IL-27R-/- and wild-type mice (n = 4–10) treated with 0.4 mg anti-IL-10R mAb or rat IgG on day 0, 2, 4, and 6 after infection with T. congolense, respectively. (B) IL-10 levels in plasma, and supernatant fluids of cultured spleen cells, and liver leukocytes from IL-27R-/- and wild-type mice (n = 4) on day 7 and 10 after infection with T. congolense. Data are presented as the mean ± SEM. The results presented are representative of 2–3 separate experiments.

Mentions: It has been shown that IL-10 is crucial for survival of mice infected with African trypanosomes through limiting inflammation [11,20]. In particular, failure to control inflammatory responses in mice infected with African trypanosomes in the absence of IL-10 signaling is associated with severe liver pathology [11,22,27]. In this regard, IL-27 has been shown to drive CD4+ T cells to produce IL-10 for downregulation of inflammation [45–47]. The similarity of the cytokine profile and liver pathology of infected mice in the absence of IL-27 signaling and IL-10 signaling [11,20] prompted us to examine whether IL-27 signaling prevented early mortality of mice infected with African trypanosomes via IL-10. We first compared the disease progression in the absence of IL-27 signaling with that in the absence of IL-10 signaling. T. congolense-infected IL-27R-/- mice and wild-type mice showed similar parasitemia and a significantly reduced survival after administration of anti-IL-10 receptor (IL-10R) mAb (p<0.01, Fig 4A). Strikingly, infected wild-type mice treated with anti-IL-10R mAb survived significantly shorter than infected IL-27R-/- mice (p<0.01, Fig 4A), suggesting that IL-27 and IL-10 may independently regulate inflammatory responses during African trypanosomiasis. Next we compared the IL-10 levels in plasma, and supernatant fluids of cultured spleen cells or liver leukocytes between IL-27R-/- and wild-type mice infected with T. congolense. There was no significant difference in IL-10 production in plasma and supernatant fluids of the cultures between IL-27R-/- and wild-type mice on day 7 after infection (Fig 4B). Surprisingly, IL-27R-/- mice even showed significantly higher amounts of IL-10 in both plasma (up to 14 folds) and supernatant fluids of cultured spleen cells or liver leukocytes on day 10 after infection (p<0.01 or <0.05, Fig 4B), demonstrating that secretion of IL-10 was strengthened, rather than impaired in IL-27R-/- mice infected with African trypanosomes, probably due to deficiency of the immune regulation mediated by IL-27 signaling in those infected IL-27R-/- mice. Taken together, these data suggested that early mortality of IL-27R-/- mice infected with African trypanosomes was not due to impaired IL-10 production.


IL-27 Signaling Is Crucial for Survival of Mice Infected with African Trypanosomes via Preventing Lethal Effects of CD4+ T Cells and IFN-γ.

Liu G, Xu J, Wu H, Sun D, Zhang X, Zhu X, Magez S, Shi M - PLoS Pathog. (2015)

IL-10 production is not impaired in IL-27R-/- (WSX-1-/-) mice infected with T. congolense.(A) Parasitemia and survival of IL-27R-/- and wild-type mice (n = 4–10) treated with 0.4 mg anti-IL-10R mAb or rat IgG on day 0, 2, 4, and 6 after infection with T. congolense, respectively. (B) IL-10 levels in plasma, and supernatant fluids of cultured spleen cells, and liver leukocytes from IL-27R-/- and wild-type mice (n = 4) on day 7 and 10 after infection with T. congolense. Data are presented as the mean ± SEM. The results presented are representative of 2–3 separate experiments.
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ppat.1005065.g004: IL-10 production is not impaired in IL-27R-/- (WSX-1-/-) mice infected with T. congolense.(A) Parasitemia and survival of IL-27R-/- and wild-type mice (n = 4–10) treated with 0.4 mg anti-IL-10R mAb or rat IgG on day 0, 2, 4, and 6 after infection with T. congolense, respectively. (B) IL-10 levels in plasma, and supernatant fluids of cultured spleen cells, and liver leukocytes from IL-27R-/- and wild-type mice (n = 4) on day 7 and 10 after infection with T. congolense. Data are presented as the mean ± SEM. The results presented are representative of 2–3 separate experiments.
Mentions: It has been shown that IL-10 is crucial for survival of mice infected with African trypanosomes through limiting inflammation [11,20]. In particular, failure to control inflammatory responses in mice infected with African trypanosomes in the absence of IL-10 signaling is associated with severe liver pathology [11,22,27]. In this regard, IL-27 has been shown to drive CD4+ T cells to produce IL-10 for downregulation of inflammation [45–47]. The similarity of the cytokine profile and liver pathology of infected mice in the absence of IL-27 signaling and IL-10 signaling [11,20] prompted us to examine whether IL-27 signaling prevented early mortality of mice infected with African trypanosomes via IL-10. We first compared the disease progression in the absence of IL-27 signaling with that in the absence of IL-10 signaling. T. congolense-infected IL-27R-/- mice and wild-type mice showed similar parasitemia and a significantly reduced survival after administration of anti-IL-10 receptor (IL-10R) mAb (p<0.01, Fig 4A). Strikingly, infected wild-type mice treated with anti-IL-10R mAb survived significantly shorter than infected IL-27R-/- mice (p<0.01, Fig 4A), suggesting that IL-27 and IL-10 may independently regulate inflammatory responses during African trypanosomiasis. Next we compared the IL-10 levels in plasma, and supernatant fluids of cultured spleen cells or liver leukocytes between IL-27R-/- and wild-type mice infected with T. congolense. There was no significant difference in IL-10 production in plasma and supernatant fluids of the cultures between IL-27R-/- and wild-type mice on day 7 after infection (Fig 4B). Surprisingly, IL-27R-/- mice even showed significantly higher amounts of IL-10 in both plasma (up to 14 folds) and supernatant fluids of cultured spleen cells or liver leukocytes on day 10 after infection (p<0.01 or <0.05, Fig 4B), demonstrating that secretion of IL-10 was strengthened, rather than impaired in IL-27R-/- mice infected with African trypanosomes, probably due to deficiency of the immune regulation mediated by IL-27 signaling in those infected IL-27R-/- mice. Taken together, these data suggested that early mortality of IL-27R-/- mice infected with African trypanosomes was not due to impaired IL-10 production.

Bottom Line: This coincides with the development of an exacerbated Th1-mediated immune response with overactivation of CD4+ T cells and strongly enhanced production of inflammatory cytokines including IFN-γ.Thus, our data identify IL-27 signaling as a novel pathway to prevent early mortality via inhibiting hyperactivation of CD4+ Th1 cells and their excessive secretion of IFN-γ during infection with African trypanosomes.These data are the first to demonstrate the essential role of IL-27 signaling in regulating immune responses to extracellular protozoan infections.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America.

ABSTRACT
African trypanosomes are extracellular protozoan parasites causing a chronic debilitating disease associated with a persistent inflammatory response. Maintaining the balance of the inflammatory response via downregulation of activation of M1-type myeloid cells was previously shown to be crucial to allow prolonged survival. Here we demonstrate that infection with African trypanosomes of IL-27 receptor-deficient (IL-27R-/-) mice results in severe liver immunopathology and dramatically reduced survival as compared to wild-type mice. This coincides with the development of an exacerbated Th1-mediated immune response with overactivation of CD4+ T cells and strongly enhanced production of inflammatory cytokines including IFN-γ. What is important is that IL-10 production was not impaired in infected IL-27R-/- mice. Depletion of CD4+ T cells in infected IL-27R-/- mice resulted in a dramatically reduced production of IFN-γ, preventing the early mortality of infected IL-27R-/- mice. This was accompanied by a significantly reduced inflammatory response and a major amelioration of liver pathology. These results could be mimicked by treating IL-27R-/- mice with a neutralizing anti-IFN-γ antibody. Thus, our data identify IL-27 signaling as a novel pathway to prevent early mortality via inhibiting hyperactivation of CD4+ Th1 cells and their excessive secretion of IFN-γ during infection with African trypanosomes. These data are the first to demonstrate the essential role of IL-27 signaling in regulating immune responses to extracellular protozoan infections.

No MeSH data available.


Related in: MedlinePlus