Inhibition of C3/C3aR Pathway Alleviates Visual and Optic Nerve Impairments in a Rat Model of Neuromyelitis Optica Spectrum Disorder

Abstract

Accumulating evidence suggests that the complement C3/C3a receptor (C3aR) pathway plays a pivotal role in the pathogenesis of neurodegenerative and autoimmune disorders, particularly neuromyelitis optica spectrum disorders (NMOSDs). Despite this, the specific pathogenic effect and mechanism of C3/C3aR pathway in NMOSD remains elusive. In this study, we demonstrated for the first time that the expression of C3aR and its upstream ligand C3 is significantly upregulated in the optic nerve of a rat model of NMOSD-related optic neuritis (NMOSD-ON). Our findings reveal that this upregulation leads to blood–brain barrier (BBB) disruption, demyelination and neuronal damage. Through the use of a novel C3aR inhibitor, JR14a, we demonstrate its effectiveness in reducing C3aR expression and mitigating pathological damage in the optic nerve. Furthermore, our transcriptome sequencing analysis of NMOSD optic nerve tissues reveals extensive enrichment of inflammation- and immune response–related pathways, with particular emphasis on the complement and coagulation cascades pathway. This study not only elucidated the crucial role of the C3-C3aR pathway in NMOSD-ON pathogenesis but also provided a new promising therapeutic target for NMOSD through C3aR pathway inhibition.