Complement receptor 3-mediated neurotoxic glial activation contributes to rotenone-induced cognitive decline in mice

• Published in: Ecotoxicology and environmental safety 2023-11, Vol.266, p.115550-115550, Article 115550
• Main Authors: Wang, Qinghui, Ruan, Zhengzheng, Jing, Lu, Guo, Ziyang, Zhang, Xiaomeng, Liu, Jianing, Tian, Lu, Sun, Wei, Song, Sheng, Hong, Jau-Shyong, Shih, Yen-Yu Ian, Hou, Liyan, Wang, Qingshan
• Format: Article
• Language: English
• Subjects: Animals; Cognitive deficit; Cognitive Dysfunction - chemically induced; Complement receptor 3; Mice; Microglia; Neuroinflammation; NF-kappa B - genetics; NF-kappa B - metabolism; Parkinson’s disease; Pesticides; Receptors, Complement; Rotenone - toxicity
• ISSN: 0147-6513; 1090-2414; 1090-2414
• DOI: 10.1016/j.ecoenv.2023.115550

Microglia-mediated chronic neuroinflammation has been associated with cognitive decline induced by rotenone, a well-known neurotoxic pesticide used in agriculture. However, the mechanisms remain unclear. This work aimed to elucidate the role of complement receptor 3 (CR3), a highly expressed receptor in microglia, in cognitive deficits induced by rotenone. Rotenone up-regulated the expression of CR3 in the hippocampus and cortex area of mice. CR3 deficiency markedly ameliorated rotenone-induced cognitive impairments, neurodegeneration and phosphorylation (Ser129) of α-synuclein in mice. CR3 deficiency also attenuated rotenone-stimulated microglial M1 activation. In microglial cells, siRNA-mediated knockdown of CR3 impeded, while CR3 activation induced by LL-37 exacerbated, rotenone-induced microglial M1 activation. Mechanistically, CR3 deficiency blocked rotenone-induced activation of nuclear factor κB (NF-κB), signal transducer and activator of transcription 1 (STAT1) and STAT3 signaling pathways. Pharmacological inhibition of NF-κB or STAT3 but not STAT1 was confirmed to suppress microglial M1 activation elicited by rotenone. Further study revealed that CR3 deficiency or knockdown also reduced rotenone-induced expression of C3, an A1 astrocyte marker, and production of microglial C1q, TNFα and IL-1α, a cocktail for activated microglia to induce neurotoxic A1 astrocytes, via NF-κB and STAT3 pathways. Finally, a small molecule modulator of CR3 efficiently mitigated rotenone-elicited cognitive deficits in mice even administered after the establishment of cognitive dysfunction. Taken together, our findings demonstrated that CR3 is a key factor in mediating neurotoxic glial activation and subsequent cognitive impairments in rotenone-treated mice, giving novel insights into the immunopathogenesis of cognitive impairments in pesticide-related Parkinsonism. •CR3 deficiency attenuates neuron damage and cognitive deficits in rotenone PD mice.•CR3 deficiency suppresses rotenone-induced microglial M1 activation.•CR3 deficiency mitigates rotenone-induced astrocyte A1 activation.•NF-κB and STAT3 mediate CR3-regulated neurotoxic glial activation and microglia-astrocyte interaction.