Impaired Stress Erythropoiesis and Susceptibility to Salmonella in AhR-Deficient Mice

Overview

Aryl hydrocarbon receptor (AhR)-deficient mice exhibit increased susceptibility to chronic Salmonella Typhimurium infection, characterized by higher bacterial loads and mortality. This vulnerability is associated with enhanced stress erythropoiesis, splenomegaly, and disrupted splenic architecture driven by elevated erythropoietin and interleukin-6 levels.

Background

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that senses environmental and endogenous signals to regulate immune responses. AhR modulates both innate and adaptive immunity and influences host defense against various pathogens. Chronic Salmonella Typhimurium infection in mice mimics human typhoid fever, often causing anemia and splenomegaly due to infection-induced stress erythropoiesis. This study investigates the role of AhR in controlling chronic Salmonella infection and the associated hematologic and immunologic changes.

Data Highlights

Key Findings

• AhR-deficient mice show impaired clearance of attenuated Salmonella Typhimurium strain TAS2010, resulting in increased bacterial burden and mortality.
• Infection induces macrocytic anemia and pronounced splenomegaly with destruction of splenic architecture in AhR−/− mice.
• AhR−/− mice exhibit a major expansion of splenic immature red blood cells, indicating exacerbated stress erythropoiesis.
• Elevated serum erythropoietin and interleukin-6 levels upon infection likely drive the enhanced stress erythropoiesis in AhR-deficient mice.
• Increased splenic stress erythroid progenitors are present even in steady state in AhR−/− mice, suggesting a predisposition to altered erythropoiesis.
• Disruption of splenic immune cell compartments due to stress erythropoiesis may impair effective host defense against Salmonella in the absence of AhR.

Clinical Implications

These findings highlight the critical role of AhR in regulating stress erythropoiesis and maintaining splenic architecture during chronic bacterial infection. Monitoring erythropoietic responses and inflammatory cytokines such as erythropoietin and IL-6 may provide insights into infection severity and host susceptibility. Therapeutic modulation of AhR signaling could represent a novel strategy to improve host defense and limit infection-induced anemia in chronic Salmonella infections.

Conclusion

AhR deficiency leads to impaired host defense against chronic Salmonella Typhimurium infection by promoting excessive stress erythropoiesis and splenic disruption. Targeting AhR pathways may enhance infection control and mitigate hematologic complications.

References

1. Original Study -- Impaired Stress Erythropoiesis and Increased Vulnerability to Salmonella Typhimurium Infection in Mice Lacking Aryl Hydrocarbon Receptor