Microglial Nox2 Plays a Key Role in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Abstract

While oxidative stress has been linked to multiple sclerosis (MS), the role of superoxide-producing phagocyte NADPH oxidase (Nox2) in central nervous system (CNS) pathogenesis remains unclear. This study investigates the impact of Nox2 gene ablation on pro- and anti-inflammatory cytokine and chemokine production in a mouse experimental autoimmune encephalomyelitis (EAE) model. Nox2 deficiency attenuates EAE-induced neural damage and reduces disease severity, pathogenic immune cells infiltration, demyelination, and oxidative stress in the CNS. The number of autoreactive T cells, myeloid cells, and activated microglia, as well as the production of cytokines and chemokines, including GM-CSF, IFNγ, TNFα, IL-6, IL-10, IL-17A, CCL2, CCL5, and CXCL10, were much lower in the Nox2−/− CNS tissues but remained unaltered in the peripheral lymphoid organs. RNA-seq profiling of microglial transcriptome identified a panel of Nox2 dependent proinflammatory genes: Pf4, Tnfrsf9, Tnfsf12, Tnfsf13, Ccl7, Cxcl3, and Cxcl9. Furthermore, gene ontology and pathway enrichment analyses revealed that microglial Nox2 plays a regulatory role in multiple pathways known to be important for MS/EAE pathogenesis, including STAT3, glutathione, leukotriene biosynthesis, IL-8, HMGB1, NRF2, systemic lupus erythematosus in B cells, and T cell exhaustion signaling. Taken together, our results provide new insights into the critical functions performed by microglial Nox2 during the EAE pathogenesis, suggesting that Nox2 inhibition may represent an important therapeutic target for MS.

Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy

“…On the other hand, the nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase (Nox2) is highly expressed by professional phagocytes, including microglia, and is essential for the activation of these cells. Upon Nox2 activation, microglia increase the chemotaxis of peripheral pathogenic immune cells into the CNS, causing demyelination and axonal damage (Hu et al, 2021). Although this latter study could benefit from a cell-specific KO strategy to investigate Nox2 in microglia, authors clearly show that Nox2-deficient mice display less inflammatory infiltrates and demyelination, as well as that microglia-mediated expression of the pool of cytokines and chemokines, is substantially decreased (Hu et al, 2021).…”

NOX2-Deficient Neutrophils Facilitate Joint Inflammation Through Higher Pro-Inflammatory and Weakened Immune Checkpoint Activities

“…When Ncf1 gene or genes of other significant components of NOX2 complex are disrupted, NOX2 complex losses the ability to produce ROS ( 11 ). The local inflammatory responses of NOX2 vary in different organs and different stimulations ( 31 , 32 ). In this study, we focused on NOX2 regulation of joint inflammation (a local inflammation).…”

Beyond the Extra Respiration of Phagocytosis: NADPH Oxidase 2 in Adaptive Immunity and Inflammation

“…Lymphocyte and microglial infiltration in the CNS was also significantly decreased compared to heterozygous and wild-type controls. Interestingly, the authors showed that only immune infiltration in the CNS is reduced, as immune cell populations in peripheral tissues such as the spleen and cervical lymph node are similar in NOX2 -/- and wild-type mice post EAE induction ( 100 ). Microglial activation was also decreased in NOX2 -/- mice, with inflammatory cytokine and chemokine secretion levels in the CNS also decreased.…”