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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

Enhanced expression of IL-27 and its crucial role in survival of mice infected with T. congolense.(A) mRNA expression levels of IL-27p28, EBI3 and WSX-1 in the liver of wild-type mice infected with T. congolense on day 7 and 10 versus day 0 (uninfected). (B) Parasitemia of IL-27R-/- (WSX-1-/-) and wild-type mice (n = 6–9) infected with T. congolense. (C) Survival of IL-27R-/- and wild-type mice (n = 6–9) infected with T. congolense. Data are presented as the mean ± SEM. The results presented are representative of 3 separate experiments.
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ppat.1005065.g001: Enhanced expression of IL-27 and its crucial role in survival of mice infected with T. congolense.(A) mRNA expression levels of IL-27p28, EBI3 and WSX-1 in the liver of wild-type mice infected with T. congolense on day 7 and 10 versus day 0 (uninfected). (B) Parasitemia of IL-27R-/- (WSX-1-/-) and wild-type mice (n = 6–9) infected with T. congolense. (C) Survival of IL-27R-/- and wild-type mice (n = 6–9) infected with T. congolense. Data are presented as the mean ± SEM. The results presented are representative of 3 separate experiments.

Mentions: To evaluate the role of IL-27 signaling during African trypanosomiasis, we first determined whether infection led to increased expression of this cytokine or its receptor. Wild-type C57BL/6 mice were infected with T. congolense, a species of African trypanosomes which are unable to leave the circulation and only live in blood vessels, causing fatal disease in cattle [4]. The mice were euthanized at day 0, 7, and 10 after infection, as parasitemia usually peaked on day 6–7 after infection [15,29]. As the liver is the major organ for clearance of the parasites [7–9,11], the liver was collected for measurement of mRNA levels of IL-27 and its receptor using real-time quantitative RT-PCR. mRNA levels of both subunits of IL-27 (IL-27p28 and EBI3) were upregulated in the liver of mice at day 7 and 10 after infection, compared to uninfected mice (Fig 1A). In contrast, mRNA levels of IL-27 receptor (WSX-1) were not affected by the infection (Fig 1A).


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)

Enhanced expression of IL-27 and its crucial role in survival of mice infected with T. congolense.(A) mRNA expression levels of IL-27p28, EBI3 and WSX-1 in the liver of wild-type mice infected with T. congolense on day 7 and 10 versus day 0 (uninfected). (B) Parasitemia of IL-27R-/- (WSX-1-/-) and wild-type mice (n = 6–9) infected with T. congolense. (C) Survival of IL-27R-/- and wild-type mice (n = 6–9) infected with T. congolense. Data are presented as the mean ± SEM. The results presented are representative of 3 separate experiments.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4519326&req=5

ppat.1005065.g001: Enhanced expression of IL-27 and its crucial role in survival of mice infected with T. congolense.(A) mRNA expression levels of IL-27p28, EBI3 and WSX-1 in the liver of wild-type mice infected with T. congolense on day 7 and 10 versus day 0 (uninfected). (B) Parasitemia of IL-27R-/- (WSX-1-/-) and wild-type mice (n = 6–9) infected with T. congolense. (C) Survival of IL-27R-/- and wild-type mice (n = 6–9) infected with T. congolense. Data are presented as the mean ± SEM. The results presented are representative of 3 separate experiments.
Mentions: To evaluate the role of IL-27 signaling during African trypanosomiasis, we first determined whether infection led to increased expression of this cytokine or its receptor. Wild-type C57BL/6 mice were infected with T. congolense, a species of African trypanosomes which are unable to leave the circulation and only live in blood vessels, causing fatal disease in cattle [4]. The mice were euthanized at day 0, 7, and 10 after infection, as parasitemia usually peaked on day 6–7 after infection [15,29]. As the liver is the major organ for clearance of the parasites [7–9,11], the liver was collected for measurement of mRNA levels of IL-27 and its receptor using real-time quantitative RT-PCR. mRNA levels of both subunits of IL-27 (IL-27p28 and EBI3) were upregulated in the liver of mice at day 7 and 10 after infection, compared to uninfected mice (Fig 1A). In contrast, mRNA levels of IL-27 receptor (WSX-1) were not affected by the infection (Fig 1A).

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