FPR2 inhibition reduces EAE severity in MS mouse model, especially combined with VLA-4 blockade

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with significant unmet needs for effective therapies. Experimental Autoimmune Encephalomyelitis (EAE) serves as a crucial mouse model for studying MS pathogenesis. Circadian rhythms, the body's intrinsic time-keeping mechanisms, are known to profoundly influence immune function and inflammation, yet their specific role in immune cell dynamics during MS development remains underexplored. Understanding how these rhythms impact immune cell infiltration into the CNS could reveal novel therapeutic targets beyond current standard-of-care treatments like VLA-4 inhibitors.

Researchers investigated the impact of circadian rhythms on EAE pathogenesis in a mouse model. They monitored circulating neutrophil levels in blood and their infiltration into the CNS. Transcriptomic analysis was performed on CNS-infiltrating neutrophils to identify time-of-day (ToD)-dependent gene expression profiles. Subsequently, they tested the therapeutic potential of pharmacologically inhibiting Formyl peptide receptor 2 (FPR2). A combinatorial treatment strategy was also evaluated, pairing FPR2 inhibition with a drug targeting VLA-4, an adhesion molecule clinically targeted by Natalizumab in MS patients, to assess additive effects on EAE disease severity.

The study revealed that circulating neutrophils significantly increased early in EAE, preceding symptom onset. Critically, these neutrophils infiltrated the central nervous system in a time-of-day (ToD)-dependent manner, with increased infiltration observed at the onset of the mice's behavioral active phase (evening). Transcriptomic analysis of these CNS-infiltrating neutrophils identified distinct ToD-dependent gene expression profiles. This analysis highlighted Formyl peptide receptor 2 (FPR2) as a promising therapeutic candidate. > Pharmacological inhibition of FPR2 led to reduced EAE disease severity, demonstrating its role in disease progression. Furthermore, combining FPR2 inhibition with a drug targeting VLA-4 (similar to Natalizumab) resulted in additive therapeutic effects, substantially reducing EAE symptoms beyond single-agent treatment.