Noradrenergic control of bone marrow and thymus by AgRP neurons is impaired in experimental multiple sclerosis

Maturation of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) and of T lymphocytes in the thymus occurs within stromal regions innervated by noradrenergic fibers of the sympathetic nervous system (SNS). However, the neuronal pathways governing noradrenergic activity in lymphoid organs remain largely unexplored. In experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), we demonstrated that noradrenergic signals promote myeloid hematopoiesis in the BM and regulate the intra-thymic frequency of regulatory T lymphocytes via β-3 adrenergic receptors (B3ARs). We further showed that B3ARs in the BM and thymus are controlled by hypothalamic neurons expressing agouti-related protein (AgRP), which are dysfunctional in EAE. Notably, elevated serum levels of AgRP correlate with disease severity and magnetic resonance imaging markers of neuroinflammation in people with MS. These findings reveal a mechanism of immune regulation mediated by noradrenergic transmission, offering potential therapeutic targets for immune-mediated diseases.