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Nramp1 drives an accelerated inflammatory response during Salmonella-induced colitis in mice
Yanet Valdez1, Guntram A Grassl, Julian A Guttman
1Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
Abstract:
A recently developed model for enterocolitis in mice involves pre-treatment with the antibiotic streptomycin prior to infection with Salmonella enterica serovar Typhimurium (S. Typhimurium). The contribution of Nramp1/Slc11a1 protein, a critical host defence mechanism against S. Typhimurium, to the development of inflammation in this model has not been studied. Here, we analysed the impact of Nramp1 expression on the early development of colitis using isogenic Nramp1(+/+) and Nramp1(-/-) mice. We hypothesized that Nramp1 acts by rapidly inducing an inflammatory response in the gut mucosa creating an antibacterial environment and limiting spread of S. Typhimurium to systemic sites. We observed that Nramp1(+/+) mice showed lower numbers of S. Typhimurium in the caecum compared with Nramp1(-/-) mice at all times analysed. Acute inflammation was much more pronounced in Nramp1(+/+) mice 1 day after infection. The effect of Nramp1 on development of colitis was characterized by higher secretion of the pro-inflammatory cytokines IFN-gamma, TNF-alpha and MIP-1alpha and a massive infiltration of neutrophils and macrophages, compared with Nramp1(-/-) animals. These data show that an early and rapid inflammatory response results in protection against pathological effects of S. Typhimurium infection in Nramp1(+/+) mice.
Insights
The Nramp1 protein rapidly induces gut inflammation, creating an antibacterial environment that protects against Salmonella Typhimurium infection. This host defense mechanism limits bacterial spread and reduces colitis severity in mice.
Area of Science:
- Immunology
- Microbiology
- Gastroenterology
Background:
- A mouse model for enterocolitis uses streptomycin pre-treatment followed by Salmonella Typhimurium infection.
- The role of Nramp1/Slc11a1 protein, a key defense against S. Typhimurium, in this colitis model is unknown.
Purpose of the Study:
- To investigate the impact of Nramp1 expression on early colitis development in a mouse model.
- To determine if Nramp1 influences S. Typhimurium infection outcomes and inflammatory responses.
Main Methods:
- Comparison of isogenic Nramp1(+/+) and Nramp1(-/-) mice.
- Quantification of S. Typhimurium in the caecum.
- Analysis of pro-inflammatory cytokine secretion (IFN-gamma, TNF-alpha, MIP-1alpha).
- Assessment of immune cell infiltration (neutrophils, macrophages).
Main Results:
- Nramp1(+/+) mice exhibited lower S. Typhimurium loads in the caecum compared to Nramp1(-/-) mice.
- Acute inflammation was significantly more pronounced in Nramp1(+/+) mice one day post-infection.
- Higher levels of IFN-gamma, TNF-alpha, and MIP-1alpha were observed in Nramp1(+/+) mice.
- Massive infiltration of neutrophils and macrophages occurred in Nramp1(+/+) mice.
Conclusions:
- Nramp1 rapidly induces an inflammatory response in the gut mucosa.
- This Nramp1-mediated inflammation creates an antibacterial environment, limiting S. Typhimurium spread.
- Early and rapid inflammation driven by Nramp1 protects against the pathological effects of S. Typhimurium infection.
