Myelin-derived peptide NSDP1 suppresses neuroinflammation, attenuates demyelination in chronic cuprizone mice via cGAS-STING.

Multiple sclerosis (MS) is a debilitating neurodegenerative disease characterized by demyelination and chronic neuroinflammation, leading to progressive neurological deficits. Current therapies primarily focus on modulating the immune system, but often fall short in promoting myelin repair or directly addressing neuroinflammation. This study investigates a novel myelin-derived peptide, NSDP1, identified as significantly downregulated in demyelinating conditions, as a potential therapeutic agent. Its mechanism, particularly concerning the cGAS-STING pathway, offers a new avenue for intervention.

Researchers utilized a cuprizone (CPZ)-induced demyelination model in male C57BL/6 mice. Proteomic analysis of this model identified NSDP1 (sequence: DTGILDSIGRFFS) as a significantly downregulated myelin basic protein-derived peptide. In vitro, NSDP1 was tested on LPS-stimulated BV2 microglial cells to assess its anti-inflammatory effects. In vivo, NSDP1 was administered via intracerebroventricular (ICV) injection to CPZ-fed mice. Primary endpoints included weight loss, demyelination in the corpus callosum, myelin protein expression (MAG, MOG), oligodendrocyte precursor cell (OPC) density, myelin sheath ultrastructure, axonal myelination efficiency, and reactive gliosis. RNA sequencing was performed to identify modulated pathways.

Proteomic analysis confirmed NSDP1 was significantly downregulated in the CPZ-induced demyelination model. In vitro, NSDP1 suppressed LPS-induced microglial activation in BV2 cells, reducing reactive oxygen species (ROS) production and downregulating pro-inflammatory markers (iNOS, TNF-α, IL-1β), while upregulating the anti-inflammatory marker Arg-1. In vivo, NSDP1 administration significantly mitigated CPZ-induced weight loss and demyelination in the corpus callosum. NSDP1 restored expression of myelin proteins (MAG, MOG), increased OPC density, improved myelin sheath ultrastructure, and enhanced axonal myelination efficiency. Furthermore, NSDP1 attenuated CPZ-induced reactive gliosis, reducing both microglial activation and astrocytic reactivity. RNA sequencing revealed NSDP1 modulated myelination-related pathways and correlated with improved locomotor recovery. Mechanistically, NSDP1 exerted its anti-inflammatory effects by inhibiting the cGAS-STING signaling pathway, as shown by reduced cGAS and STING expression in LPS-stimulated BV2 cells. > The effects of NSDP1 on ROS and pro-inflammatory cytokine release were reversed by the STING activator DMX and mimicked by the STING inhibitor SN-011, confirming cGAS-STING as a key target.