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Microglial Nox2 Plays a Key Role in the Pathogenesis of Experimental Autoimmune Encephalomyelitis
Chih-Fen Hu1,2, San-Pin Wu3, Gu-Jiun Lin4
1Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
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.
Insights
Phagocyte NADPH oxidase (Nox2) deficiency reduces central nervous system damage in a multiple sclerosis model. This suggests Nox2 inhibition could be a therapeutic target for multiple sclerosis (MS).
Area of Science:
- Neuroimmunology
- Oxidative Stress
- Central Nervous System (CNS) Pathogenesis
Background:
- Oxidative stress is implicated in multiple sclerosis (MS) pathogenesis.
- The specific role of superoxide-producing phagocyte NADPH oxidase (Nox2) in the CNS during MS is not fully understood.
Purpose of the Study:
- To investigate the impact of Nox2 gene ablation on immune responses and CNS pathology in a mouse model of experimental autoimmune encephalomyelitis (EAE).
- To identify Nox2-dependent inflammatory pathways in microglia relevant to MS pathogenesis.
Main Methods:
- Utilized a mouse experimental autoimmune encephalomyelitis (EAE) model.
- Compared wild-type and Nox2-deficient (Nox2-/-) mice.
- Analyzed cytokine and chemokine profiles, immune cell infiltration, demyelination, and oxidative stress in CNS tissues.
- Performed RNA-sequencing (RNA-seq) on microglia and conducted gene ontology and pathway enrichment analyses.
Main Results:
- Nox2 deficiency significantly attenuated EAE severity, reducing neural damage, immune cell infiltration, demyelination, and oxidative stress in the CNS.
- Pro- and anti-inflammatory cytokine and chemokine levels, along with immune cell populations (autoreactive T cells, myeloid cells, microglia), were significantly lower in the CNS of Nox2-/- mice.
- RNA-seq identified novel Nox2-dependent pro-inflammatory genes in microglia and revealed Nox2's regulatory role in key MS/EAE pathways.
Conclusions:
- Microglial Nox2 plays a critical role in regulating neuroinflammation and CNS pathogenesis during EAE.
- Nox2 deficiency confers protection against EAE, highlighting its pathogenic contribution.
- Targeting Nox2 may represent a promising therapeutic strategy for managing multiple sclerosis.
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