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Nitric oxide and the Th2 response combine to prevent severe hepatic damage during Schistosoma mansoni infection
L R Brunet1, M Beall, D W Dunne
1Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Abstract:
During infection with Schistosoma mansoni, NO production increases following the deposition of parasite eggs in the liver. In wild-type C57BL/6 mice, NO levels peak during the sixth week of infection and are subsequently down-regulated. Inducible NO synthase (iNOS) mRNA was found in diseased liver tissue along with TNF-alpha and IFN-gamma, which are known promoters of iNOS expression. Mice treated with aminoguanidine, a selective inhibitor of iNOS, exhibited cachexia and exacerbated liver pathology, suggesting that NO limits hepatocyte damage when the liver is first exposed to eggs. Hepatic iNOS is up-regulated in SCID mice, indicating that NO production is part of an innate response. Studies with infected highly susceptible IL-4-/- mice revealed that prolonged NO production is in itself deleterious and that a major function of the Th2 response, which is severely compromised in the absence of IL-4, is to regulate NO production. In these animals, plasma NO levels are high compared with those in infected wild-type mice and remain elevated until death. Nevertheless, the underlying importance of NO is illustrated by the finding that aminoguanidine treatment leads to more severe liver disease and reduced time to death in infected IL-4-/- mice.
Insights
Nitric oxide (NO) initially protects against liver damage during Schistosoma mansoni infection but prolonged production, especially without IL-4, proves harmful. Regulating NO is crucial for managing infection-induced liver pathology.
Area of Science:
- Immunology
- Parasitology
- Hepatology
Background:
- Schistosoma mansoni infection increases nitric oxide (NO) production in the liver.
- Inducible NO synthase (iNOS) mRNA, TNF-alpha, and IFN-gamma are present in infected liver tissue.
- NO's role in Schistosoma mansoni infection is complex, potentially protective early on but harmful later.
Purpose of the Study:
- To investigate the dual role of NO in Schistosoma mansoni-induced liver pathology.
- To understand the regulation of NO production during infection, particularly concerning the Th2 response.
- To determine the impact of iNOS inhibition on liver disease severity.
Main Methods:
- Utilizing wild-type C57BL/6 mice, SCID mice, and IL-4 knockout (IL-4-/-) mice infected with Schistosoma mansoni.
- Administering aminoguanidine, a selective iNOS inhibitor, to assess NO's protective or detrimental effects.
- Monitoring NO levels, iNOS mRNA expression, and liver pathology in different mouse models.
Main Results:
- Aminoguanidine treatment exacerbated liver pathology in wild-type mice, suggesting NO limits early hepatocyte damage.
- Hepatic iNOS was upregulated in SCID mice, indicating NO is part of an innate immune response.
- In IL-4-/- mice, prolonged NO production was deleterious, leading to higher plasma NO levels and increased mortality, which was worsened by aminoguanidine.
Conclusions:
- NO plays a dichotomous role in Schistosoma mansoni liver disease: protective in the early phase and detrimental with prolonged production.
- The Th2 immune response, dependent on IL-4, is critical for regulating excessive NO production.
- Targeting NO production requires careful consideration of the infection stage and host immune status.