Diurnal regulation of brain innate immunity across the lifespan 4242

Abstract Description The immune system functions rhythmically, distributing tissue defense and repair across the day-night cycle. While the central nervous system (CNS) is a highly rhythmic milieu, how its unique immune landscape may be tuned to time-of-day is less well understood. We set out to profile CNS immune cells by single-cell RNA sequencing of the brain and leptomeninges every six hours around a single day-night cycle, massively enriching for rare, tissue-resident leukocytes. Border-associated macrophages (BAMs) emerged as highly rhythmic cells, by far surpassing parenchyma-dwelling microglia. Differentially expressed genes involved functions such as scavenger receptor expression, complement signaling, and antigen presentation. Functional assays revealed that BAM engulfment was also rhythmic: uptake of extracellular substrates including amyloid-beta was almost doubled during the light cycle, the murine rest phase. Diurnal changes in engulfment were regulated by the master circadian oscillator Bmal1 and mediated by the fast-recycling mannose receptor CD206, suggesting that BAMs may be tuned by the clock to synchronize endocytosis to periods of enhanced fluid flow in the CNS. BAMs from aged mice exhibited dysregulated clock gene expression, attenuated rhythmicity in engulfment, and impaired overall endocytic capacity, a potential avenue by which aging may precipitate neuroinflammation and diseases of protein aggregation. Funding Sources Supported by NIA 5T32AG000222; Simons Foundation; Cure Alzheimer’s Fund Topic Categories Neuroimmunology (NEUR)