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Neutrophil depletion exacerbates experimental Chagas' disease in BALB/c, but protects C57BL/6 mice through
L Chen1, T Watanabe, H Watanabe
1Department of Immunology and Parasitology, Yamagata University School of Medicine, Yamagata, Japan.
Insights
Neutrophils play opposing roles in experimental Chagas
Area of Science:
- Immunology
- Parasitology
- Infectious Diseases
Background:
- Chagas' disease, caused by Trypanosoma cruzi, presents complex host-pathogen interactions.
- The role of neutrophils in modulating the immune response during T. cruzi infection remains incompletely understood.
- Murine models are crucial for dissecting the cellular and molecular mechanisms underlying Chagas' disease pathogenesis.
Purpose of the Study:
- To investigate the differential roles of neutrophils in BALB/c and C57BL/6 mice infected with Trypanosoma cruzi.
- To determine how neutrophil depletion impacts Th1/Th2 cytokine profiles and disease outcomes in experimental Chagas' disease.
- To analyze the cytokine and chemokine expression profiles of neutrophils isolated from infected mice.
Main Methods:
- Peripheral neutrophils were depleted using a monoclonal antibody in BALB/c and C57BL/6 mice prior to T. cruzi infection.
- Disease severity was assessed, and mRNA expression of key cytokines (IL-2, IFN-gamma, IL-12p40, TNF-alpha, IL-10) and chemokines (MIG, MIP-1alpha) was quantified in splenic tissue.
- Cytokine and chemokine mRNA expression was also analyzed in neutrophils isolated from infected mice.
Main Results:
- Neutrophil depletion exacerbated disease in BALB/c mice, correlating with decreased Th1 cytokine and increased IL-10 expression.
- In contrast, neutrophil depletion conferred resistance in C57BL/6 mice, enhancing Th1 cytokine expression despite increased IL-10.
- Neutrophils from BALB/c mice expressed Th1-associated molecules (IL-12p40, IFN-gamma, TNF-alpha, MIG, MIP-1alpha), while C57BL/6 neutrophils expressed TNF-alpha, MIP-1alpha, and IL-10 but not IL-12p40 or IFN-gamma.
Conclusions:
- Neutrophils exhibit strain-dependent, opposing roles in experimental Chagas' disease, influencing disease exacerbation or protection.
- These differential roles are likely mediated by neutrophils' capacity to modulate the Th1/Th2 immune balance in distinct directions.
- Understanding neutrophil function is critical for developing targeted immunotherapies for Chagas' disease.
Abstract:
To elucidate the roles of neutrophils in experimental Chagas' disease, we depleted the peripheral neutrophils in BALB/c and C57BL/6 mice with a monoclonal antibody 1 day before Trypanosoma cruzi infection. Neutrophil depletion in BALB/ c mice resulted in exacerbation of the disease and decreased expression of mRNA for Th1 cytokines, including IL-2 and IFN-gamma, IL-12p40 and TNF-alpha in their spleens after the infection, while a Th2 cytokine, IL-10, increased especially 1 day after infection. Neutrophils from infected BALB / c mice expressed mRNA for IL-12p40, IFN-gamma, TNF-alpha and Th1 chemoattractive chemokines, monokine induced by IFN-gamma (MIG) and macrophage inflammatory protein-1alpha (MIP-1alpha ). In contrast, in C57BL/6 mice neutrophil depletion induced resistance to the disease and enhanced the expression of the above Th1 cytokines, although IL-10 mRNA in neutrophil-depleted C57BL/6 mice was also higher than in control mice. Neutrophils from C57BL/6 mice did not express IL-12p40, IFN-gamma and MIG but expressed TNF-alpha, MIP-1alpha and IL-10. Therefore, neutrophils may play opposite roles in these two strains of mice with respect to protection versus exacerbation of T. cruzi infection, possibly through modulating the Th1/Th2 dichotomy in different directions.
