S100A8/A9 blockade attenuates autoimmune neuroinflammation by regulating the heterogeneity and function of neutrophils.

Patients with multiple sclerosis (MS) exhibit elevated levels of calprotectin S100A8/A9 in the blood, bone marrow (BM), and feces. However, the potential of targeting S100A8/A9 as a therapeutic approach for MS treatment remains to be fully elucidated. In this study, using an experimental autoimmune encephalomyelitis (EAE) model of MS, we found that inhibiting S100A8/A9 using paquinimod attenuated the EAE disease severity, which is associated with decreased splenic neutrophils, particularly the immature Ly6GhiCD101-subset. Detailed analysis of neutrophil subsets revealed a decreased banded-to-segmented neutrophil ratio in the paquinimod group. Furthermore, we found that paquinimod treatment decreases neutrophil accumulation, which is associated with suppressed neutrophil production. Our findings highlight the therapeutic potential of targeting S100A8/A9 to modulate neutrophil heterogeneity and mitigate autoimmune pathology in MS/EAE treatment.