NADPH Oxidase 4 Deficiency Enhances Dendritic Cell-mediated IL-12 Production and Th1 Responses in Mycobacterium tuberculosis Infection.

Abstract

Background: Mycobacterium tuberculosis (Mtb) infection triggers oxidative stress, necessitating host mechanisms to maintain redox balance. The NADPH oxidase (NOX) family, which produces reactive oxygen species, plays an integral part in this process. While the protective role of NOX2 in Mtb infection is well-studied, the function of NOX4 remains unclear.

Methods: To investigate the impact of NOX4, we infected C57BL/6 wild-type (WT) and NOX4-deficient (Nox4^-/-) mice with the Mtb K strain, assessing bacterial burdens, lung pathology, and immune responses. Then, we analyzed cytokine production and signaling pathways to explore the interaction between dendritic cells (DCs) and T cells.

Results: Nox4^-/- mice exhibited reduced bacterial burden and milder lung pathology compared to WT mice, accompanied by increased DC infiltration and a higher frequency of CD4⁺ T cells of the Th1 subset that secrete interferon-gamma (IFN-γ) in the lungs. Interestingly, ex vivo experiments showed no significant difference in IFN-γ production by T cells from WT and Nox4^-/- mice when activated using antibody-coated beads. However, Mtb-infected bone marrow-derived DCs (BMDCs) from Nox4^-/- mice markedly enhanced IFN-γ production in WT T cells. Further investigation into the role of NOX4 in DCs revealed that BMDCs from Nox4^-/- mice infected with Mtb produced significantly higher levels of IL-12. This elevation was attributed to enhanced activation of IRF1, mediated by the AKT/GSK-3β signaling pathway.

Conclusion: NOX4 negatively regulates IL-12 production in Mtb-infected DCs, suppressing Th1-mediated immunity. Its absence enhances Th1 responses, improves immune control of Mtb. Targeting NOX4 may improve tuberculosis outcomes by strengthening host immunity.