S100A9 as a potential novel target for neuromyelitis optica spectrum disorder

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system that predominantly affects the optic nerves and spinal cord, with the pathological process largely attributed to autoantibodies targeting aquaporin-4 (AQP4). Research has indicated that, in addition to adaptive immune responses associated with AQP4-IgG, innate immune cells such as monocytes/macrophages not only initiate acute-phase inflammation but also contribute to demyelinating lesions via extensive infiltration, highlighting their key pathogenic role in NMOSD. In our research, RNA-seq and bioinformatics analysis identified 326 differentially expressed genes (DEGs) in NMOSD. Immune infiltration analysis revealed that monocytes were the immune cells with the most significantly increased infiltration. Through further screening, 38 immune-related DEGs were identified, and 10 hub genes were found in subsequent protein-protein interaction (PPI) network analysis, among which S100A9 was particularly notable. Gene Set Enrichment Analysis (GSEA) indicated that S100A9 might influence the function of monocytes/macrophages in NMOSD via the Toll-like Receptor and NF-κB signaling pathways. Further experiments demonstrated that S100A9 expression was elevated in NMOSD patients. Functionally, it was found that extracellular S100A9 secretion promoted macrophage polarization toward the M1 phenotype, macrophage proliferation, and the production of inflammatory and chemotactic factors. Mechanistically, exogenous S100A9 mediated the neuroinflammatory response in NMOSD by activating the TLR4/MyD88/NF-κB pathway, regulating macrophage function. This study highlights S100A9 as a possible treatment target and a marker for predicting the disease, offering a new understanding of how NMOSD is diagnosed and develops.

Bioinformatics analysis; Neuroinflammation; RNA-seq; S100A9; THP-1; TLR4/MyD88/NF-κB pathway.