NRF2 inhibition of alveolar macrophage MHC II expression during Mycobacterium tuberculosis infection 2254024

Abstract

Abstract Introduction Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a major global health concern. Alveolar macrophages (AMs) are the initial host targets of Mtb. During Mtb infection, AMs up-regulate a NRF2 regulated cell-protective program, which is detrimental to host control and impedes AM activation, including MHC II expression. MHC II is critical for CD4+ T cell activation and host immunity during Mtb infection. We hypothesized that NRF2 regulates AM antigen presentation and their ability to present to T cells. Methods To investigate the importance of NRF2-mediated inhibition of MHC class II expression in AMs, we used an in vivo murine aerosol infection model and in vitro murine macrophage models, including primary AMs, ex vivo murine AMs (mexAMs) derived from WT, NRF2 KO (NRF2-/-), or NRF2 myeloid-conditional knock-out strains, and bone marrow-derived macrophages (BMDMs) as a model of recruited macrophages. Results We found that NRF2 inhibits MHC II, but not MHC I, specifically in AMs, following Mtb infection in vitro and in vivo. NRF2 dampens Ciita and H2-Ab1 gene expression in uninfected AMs, and MHC II inhibition by NRF2 is retained following innate stimuli and IFNγ exposure. Notably, NRF2 expression in Mtb-infected AMs eventually impedes their ability to activate ESAT6-specific CD4+ T cells. Conclusion Thus, although NRF2 expression enhances cell-protective functions, it has the unexpected consequence of limiting innate-adaptive crosstalk, which can impair CD4+ T cell activation and host immunity during Mtb infection. Targeting NRF2 signaling pathways in AMs represents a promising avenue for therapeutic interventions aimed at enhancing host immune defenses to limit bacterial growth. Funding Source R21AI163809 NIH/NIAID, 1R01AI77653-OIAI Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)