Farnesoid X Receptor in Mice Prevents Severe Liver Immunopathology During Lymphocytic Choriomeningitis Virus Infection.

BACKGROUND: Bile acids (BAs) are steroid molecules that are synthesized in the liver. In addition to their important role as a surfactant in solubilizing lipids and promoting the absorption of lipids in the gastrointestinal tract, they act as inflammagens. The role of BAs and their receptor farnesoid X receptor (FXR) during viral infection has not been studied in detail. METHODS: By using FXR-deficient mice, we investigated the role of bile acid receptor FXR during infection with lymphocytic choriomeningitis virus (LCMV). The importance of FXR in inducing IFN-I and monocytes proliferation were investigated and viral titers and T cell exhaustion were analyzed at different time points. RESULTS: This study shows that controlled levels of BAs activate FXR in hepatocytes and FXR in response upregulates the production of type I interferon. In turn, FXR maintains BAs within a balanced range to inhibit their toxic effects. The absence of FXR results in high levels of BAs, which inhibit the proliferation of monocytes and result in a defect in viral elimination, consequently leading to T cell exhaustion. CONCLUSION: We found that FXR contributes to IFN-I production in hepatocytes and balances BA levels to inhibit their toxic effects on monocytes.

Oxidized ATP inhibits T-cell-mediated autoimmunity.

T cells directed against self antigens play an important role in several autoimmune diseases. The available immunosuppressive compounds used to treat autoimmune diseases are limited, and often they have side effects that limit their application. T cells express ATP receptors, which could be new target molecules to treat autoimmune disease. Here we analyzed the effect of oxidized ATP (oxATP), an inhibitor of the ATP receptor P2rx7, in different murine models of T-cell-mediated autoimmune diseases. Treatment with oxATP inhibited proliferation and effector function of T cells. In the systems we used, oxATP did not obviously interfere with the innate immune response, but strongly reduced antigen-specific T-cell responses. This treatment ameliorated T-cell-mediated autoimmune type I diabetes and autoimmune encephalitis in mice. In conclusion, oxATP was found to strongly inhibit activated T cells and could thus be used to target T-cell-mediated autoimmune disease.

Tissue macrophages suppress viral replication and prevent severe immunopathology in an interferon-I-dependent manner in mice.

UNLABELLED: The innate immune response plays an essential role in the prevention of early viral dissemination. We used the lymphocytic choriomeningitis virus model system to analyze the role of tissue macrophages/Kupffer cells in this process. Our findings demonstrated that Kupffer cells are essential for the efficient capture of infectious virus and for preventing viral replication. The latter process involved activation of Kupffer cells by interferon (IFN)-I and prevented viral spread to neighboring hepatocytes. In the absence of Kupffer cells, hepatocytes were not able to suppress virus replication, even in the presence of IFN-I, leading to prolonged viral replication and severe T cell-dependent immunopathology. CONCLUSION: Tissue-resident macrophages play a crucial role in early viral capture and represent the major liver cell type exhibiting responsiveness to IFN-I and providing control of viral replication.