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

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 alpha-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 xB (NF-xB), signal transducer and activator of transcription 1 (STAT1) and STAT3 signaling pathways. Pharmacological inhibition of NF-xB 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, TNF alpha and IL-1 alpha, a cocktail for activated microglia to induce neurotoxic A1 astrocytes, via NF-xB 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.

Automated summary

This study demonstrates the key role of CR3 in mediating neurotoxic glial activation and subsequent cognitive impairments in rotenone-treated mice. CR3 deficiency or knockdown reduces the production of neurotoxic cells induced by rotenone, thus improving cognitive abilities in mice. The NF-xB and STAT3 pathways are involved in this process.