Neuropsychiatric involvement in lupus is associated with the Nogo-a/NgR1 pathway

•Nogo-a product was detected in the CSF of patients with neuropsychiatric lupus•Nogo-a-positive cells and pro-inflammatory cytokines were seen in aged MRL/lpr mice•Aged MRL/lpr mice also showed impairments in myelin sheath, memory, and cognition•Nogo-66 antagonism downregulated pro-inflammatory factors and promoted myelin repair and improved memory and cognition•The Nogo-a/NgR1 pathway is involved in neuropsychiatric lupus

Neuroinflammation- and neurodegeneration-induced nerve injury may represent important components of neuropsychiatric lupus (NPSLE). Myelin-associated neurite outgrowth inhibitor (Nogo)-a and its receptor, NgR1, limit recovery of the adult central nervous system after injury. We detected a soluble Nogo-a product in the cerebral spinal fluid of patients with NPSLE. In a mouse model of lupus, aging was associated with an increase in Nogo-a positive neurons, diminished myelin sheaths, enhanced pro-inflammatory cytokines, and impaired cognition and memory. Treatment with the Nogo-66 antagonist promoted myelin repair, improved cognition and memory, and downregulated pro-inflammatory factors. Our data imply the Nogo-a/NgR1 pathway is involved in NPSLE.