An ARG1-associated immunometabolic program in bone marrow PMN-MDSC-like cells in multiple sclerosis and experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Recent work indicates that bone-marrow hematopoietic niches sense CNS autoimmunity and enhance myeloid output. However, whether MS bone marrow contains an immunometabolic PMN-MDSC-like state, and whether related ARG1-associated observations can be examined in a cross-species EAE context, remains unclear.

We reanalyzed single-cell RNA sequencing data from treatment-naive patients with MS and healthy controls, focusing on myeloid states. We used donor-aware proportion analysis, trajectory inference, module scoring, donor-pseudobulk pathway enrichment, expression-based transcription-factor prioritization, co-expression analysis, ligand-target inference, and ARG1 virtual perturbation. We also quantified flow-gated bone marrow PMN-MDSCs and ARG1 protein in MOG35-55-induced EAE and tested systemic prophylactic oral nor-NOHA.

MS bone marrow showed myeloid skewing and a heterogeneous PMN-MDSC-like transcriptional state, while donor-level subtype proportions were comparable between groups. Neutrophil degranulation showed the strongest BH-supported donor-pseudobulk enrichment, and expression-based regulatory and communication analyses converged on an ARG1-associated network. In EAE, flow-gated bone-marrow PMN-MDSCs and ARG1 protein were increased, and systemic prophylactic nor-NOHA was associated with lower clinical scores and reduced spinal-cord pathology.

These data identify an ARG1-associated immunometabolic program in bone-marrow PMN-MDSC-like cells and connect the human transcriptional landscape with ARG1 protein expression and pharmacologic responses in EAE. Together, the findings establish ARG1-associated immunometabolism as a focused pathway for mechanistic and translational investigation.