Neuronal NR4A1 and complement coordinate synaptic stripping by microglia in lupus

Abstract Up to 75% of systematic lupus erythematosus (SLE) patients experience neuropsychiatric (NP) symptoms, called neuropsychiatric SLE (NPSLE), yet the underlying mechanisms remain elusive. Here we showed that complement-coordinated elimination of synapses participated in NPSLE in MRL/lpr mice, a lupus-prone murine model. We demonstrated that lupus mice developed increased anxiety-like behaviors and persistent phagocytic microglia reactivation before overt peripheral lupus pathology. In lupus brain, C1q was increased and localized at synaptic terminals, causing the apposition of phagocytic microglia, ensuing synaptic loss, and neurological disease. We further determined that neuronal Nr4a1 signaling was essential for attracting C1q synaptic deposition and then apposition of phagocytic microglia, resulting in synaptic loss and neurological disease. Minocycline-deactivated microglia, antibody-blocked C1q, or neuronal Nr4a1 restored protected lupus mice from synapse loss and NP manifestations. Our findings revealed an active role of neurons in coordinating microglia-mediated synaptic loss and highlight neuronal Nr4a1 and C1q as critical components amenable to pharmacological intervention in NPSLE.