Fundam Res. 2025 Nov 7;6(5):3491-3506. doi: 10.1016/j.fmre.2025.11.001. eCollection 2026 Sep.
ABSTRACT
Abundant evidence indicates that the interaction between astrocytes and microglia through the C3-C3a receptor (C3aR) pathway is a crucial contributor to the pathogenesis of neurodegenerative and autoimmune disorders, such as neuromyelitis optica (NMO). However, the role of C3aR in microglia in modulating inflammation related to local lesions and neurological dysfunctions in NMO remains unclear. In this study, we reveal for the first time that the expression of C3aR on microglia is positively correlated with microglial activation, proinflammatory cytokine secretion, and complement deposition, which results in the typical NMO-like lesion characterized by astrocyte injury with aquaporin 4 (AQP4) loss, demyelination, and motor neuron loss, as well as cognitive impairments, visual defects, and locomotor deficits in different models of NMO. The knockdown of C3aR or the use of a C3aR antagonist, both ex vivo and in vivo, effectively attenuates neuroinflammation, alleviates pathological lesions, and rescues neurological functions. Mechanistically, we identify STAT3 as a downstream target of microglial C3aR signaling that functionally mediates NMO pathogenesis. Blocking the C3aR/STAT3 cascade restores motor and visual functions by reducing the release of proinflammatory factors. Taken together, our study demonstrates a key role of the C3aR-STAT3 pathway in regulating neuroinflammation in NMO pathology and provides potential targets for therapeutic intervention.
PMID:42846538 | PMC:PMC13644504 | DOI:10.1016/j.fmre.2025.11.001