Proceedings of the National Academy of Sciences of the United States of AmericaJul 8, 2026

Daily patterns in immune cells reveal treatment targets in multiple sclerosis

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jul 9, 2026

Abstract

Circulating neutrophils significantly increase early in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis.

Neutrophils infiltrate the central nervous system in a time-of-day-dependent manner, with increased infiltration during the evening.
Transcriptomic analysis of CNS-infiltrating neutrophils shows distinct gene expression profiles that vary with the time of day.
Formyl peptide receptor 2 (FPR2) is identified as a potential therapeutic target, as inhibiting it reduces EAE disease severity.
Combining FPR2 inhibition with a drug targeting VLA-4 (Natalizumab) results in additive effects that significantly reduce EAE symptoms.
These findings suggest a critical role for circadian immune cell dynamics in the development of EAE.

Simplified

Circadian rhythms are intrinsic time-keeping mechanisms that play a critical role in tuning immunity. Here, we investigated the impact of circadian rhythms on the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS). We demonstrate that circulating neutrophils in blood significantly increase early in EAE, prior to symptoms onset. Importantly, we found that these cells infiltrate the central nervous system (CNS) in a time-of-day (ToD)-dependent manner, with increased infiltration at the onset of the behavioral active phase of the mice (evening). Transcriptomic analysis of CNS-infiltrating neutrophils revealed distinct ToD-dependent gene expression profiles, which identified Formyl peptide receptor 2 (FPR2) as a potential therapeutic candidate, since pharmacological inhibition of FPR2 led to reduced EAE disease severity. Furthermore, combinatorial treatment with a drug that targets VLA-4 (used in clinical practice under the trade name Natalizumab to treat MS) led to additive effects, substantially reducing EAE symptoms. Together, these findings highlight the importance of circadian immune cell dynamics during EAE development and provide a characterization of the circadian immune landscape in an animal model of MS, identifying potential targets for MS therapies.