(W1183) NADPH Oxidase 4 Deficiency Enhances IL-12 Production and Th1 Responses in Mycobacterium tuberculosis Infection through Bone Marrow-Derived Dendritic Cells

Abstract: Mycobacterium tuberculosis (Mtb) infection induces oxidative stress, necessitating host regulatory mechanisms to maintain redox balance. The NADPH oxidase (NOX) family modulates reactive oxygen species production, yet while NOX2 has been extensively studied in Mtb infection, the role of NOX4 remains unclear. Given the importance of dendritic cells (DCs) in orchestrating adaptive immune responses, we investigated how NOX4 influences DC function and its subsequent effects on host immunity. Using NOX4-deficient (Nox4-/-) and wild-type (WT) mice infected with Mtb, we found that Nox4-/- mice exhibited reduced bacterial burden and milder lung pathology, accompanied by increased DC infiltration and a higher frequency of interferon-gamma (IFN-γ)-producing CD4+ T cells. Ex vivo experiments revealed that while T cells from WT and Nox4-/- mice exhibited comparable IFN-γ production when stimulated directly, Mtb-infected bone marrow-derived DCs (BMDCs) from Nox4-/- mice significantly enhanced IFN-γ production in WT T cells. Further analysis demonstrated that NOX4 deficiency led to increased IL-12 production in DCs through enhanced activation of IRF1, mediated by the AKT/GSK-3β signaling pathway. These findings suggest that NOX4 negatively regulates IL-12 production in Mtb-infected DCs, thereby suppressing Th1-mediated immunity. Notably, since BMDCs are derived from hematopoietic stem and progenitor cells (HSPCs), our results highlight the potential for modulating NOX4 in stem cell-derived DCs to enhance immune responses. This could open avenues for utilizing stem cell-based immunotherapies to improve host defense against tuberculosis and optimize vaccine efficacy. Given the critical role of DCs in immune regulation, targeting NOX4 may offer a novel strategy for harnessing stem cell-derived immune cells to combat infectious diseases.

Funding Source: This work was supported by the NRF grants funded by MSIT [RS-2023-00208115] and the Ministry of Education [RS-2023-00246091]

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