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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-27 signaling is required to prevent liver immunopathology during infection with T. congolense.(A) Macroscopic examination of liver on day 10 after infection with T. congolense revealed the presence of extensive pale geographic areas in IL-27R-/- (WSX-1-/-), but not wild-type mice (n = 4). (B) Hematoxylin and eosin staining showing loss of hepatocyte cellular architecture in the liver of IL-27R-/-, but not wild-type mice (n = 4) on day 10 after infection with T. congolense (original magnification ×40). (C) Serum ALT activities were assessed in 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 separate experiments.
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ppat.1005065.g003: IL-27 signaling is required to prevent liver immunopathology during infection with T. congolense.(A) Macroscopic examination of liver on day 10 after infection with T. congolense revealed the presence of extensive pale geographic areas in IL-27R-/- (WSX-1-/-), but not wild-type mice (n = 4). (B) Hematoxylin and eosin staining showing loss of hepatocyte cellular architecture in the liver of IL-27R-/-, but not wild-type mice (n = 4) on day 10 after infection with T. congolense (original magnification ×40). (C) Serum ALT activities were assessed in 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 separate experiments.

Mentions: We and others have previously shown that excessive systemic inflammatory responses of mice infected with African trypanosomes are associated with severe liver damage [11,22,43,44]. In addition, the liver is the primary organ of trypanosome clearance [7,9,11]. Therefore, we next evaluated effects of IL-27 signaling on liver pathology during the course of infection with the parasites. IL-27R-/- mice, but not wild-type mice, showed extensive pale geographic areas highly suggestive of necrosis on day 10 after infection with T. congolense (Fig 3A). Microscopic examination of the liver of infected IL-27R-/- mice revealed many large areas with loss of hepatocyte cellular architecture and an infiltration of inflammatory cells (Fig 3B). By contrast, these pathological changes were not observed in the liver of infected wild-type mice (Fig 3B). To further characterize the liver pathology, we measured the serum activities of alanine aminotransferase (ALT) of mice during T. congolense infection. As shown in Fig 3C, IL-27R-/- mice had significantly higher serum activities of ALT than wild-type mice on both day 7 and day 10 after infection (p<0.05), indicating death of hepatocytes and release of cytosolic enzymes. These results demonstrated that IL-27 signaling played a major role in prevention of the liver pathology that was associated with enhanced systemic inflammatory responses.


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-27 signaling is required to prevent liver immunopathology during infection with T. congolense.(A) Macroscopic examination of liver on day 10 after infection with T. congolense revealed the presence of extensive pale geographic areas in IL-27R-/- (WSX-1-/-), but not wild-type mice (n = 4). (B) Hematoxylin and eosin staining showing loss of hepatocyte cellular architecture in the liver of IL-27R-/-, but not wild-type mice (n = 4) on day 10 after infection with T. congolense (original magnification ×40). (C) Serum ALT activities were assessed in 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 separate experiments.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1005065.g003: IL-27 signaling is required to prevent liver immunopathology during infection with T. congolense.(A) Macroscopic examination of liver on day 10 after infection with T. congolense revealed the presence of extensive pale geographic areas in IL-27R-/- (WSX-1-/-), but not wild-type mice (n = 4). (B) Hematoxylin and eosin staining showing loss of hepatocyte cellular architecture in the liver of IL-27R-/-, but not wild-type mice (n = 4) on day 10 after infection with T. congolense (original magnification ×40). (C) Serum ALT activities were assessed in 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 separate experiments.
Mentions: We and others have previously shown that excessive systemic inflammatory responses of mice infected with African trypanosomes are associated with severe liver damage [11,22,43,44]. In addition, the liver is the primary organ of trypanosome clearance [7,9,11]. Therefore, we next evaluated effects of IL-27 signaling on liver pathology during the course of infection with the parasites. IL-27R-/- mice, but not wild-type mice, showed extensive pale geographic areas highly suggestive of necrosis on day 10 after infection with T. congolense (Fig 3A). Microscopic examination of the liver of infected IL-27R-/- mice revealed many large areas with loss of hepatocyte cellular architecture and an infiltration of inflammatory cells (Fig 3B). By contrast, these pathological changes were not observed in the liver of infected wild-type mice (Fig 3B). To further characterize the liver pathology, we measured the serum activities of alanine aminotransferase (ALT) of mice during T. congolense infection. As shown in Fig 3C, IL-27R-/- mice had significantly higher serum activities of ALT than wild-type mice on both day 7 and day 10 after infection (p<0.05), indicating death of hepatocytes and release of cytosolic enzymes. These results demonstrated that IL-27 signaling played a major role in prevention of the liver pathology that was associated with enhanced systemic inflammatory responses.

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