Abstract
BackgroundThe loss of locus coeruleus noradrenergic (LC/NE) neurons in the brainstem is reported in multiple neurodegenerative disorders, including Parkinson’s disease (PD). However, the mechanisms remain unclear. Strong evidence suggested that microglia-mediated neuroinflammation contributes to neurodegeneration in PD. We recently recognized integrin CD11b, the α-chain of macrophage antigen complex-1 (Mac-1, also called CR3), as a key regulator for microglial activation. However, whether CD11b is involved in LC/NE neurodegeneration in PD remains to be investigated.MethodsLC/NE neurodegeneration and microglial activation were compared between wild type (WT) and CD11b KO mice after treated with paraquat and maneb, two pesticides that widely used to create PD model. The role of NLRP3 inflammasome in CD11b-mediated microglial dysfunction and LC/NE neurodegeneration was further explored. LC/NE neurodegeneration, microglial phenotype, and NLRP3 inflammasome activation were determined by using Western blot, immunohistochemistry, and RT-PCR technologies.ResultsParaquat and maneb co-exposure elevated the expressions of CD11b in the brainstem of mice, and CD11b knockout significantly reduced LC/NE neurodegeneration induced by paraquat and maneb. Mitigated microglial activation and gene expressions of proinflammatory cytokines were also observed in paraquat and maneb-treated CD11b−/− mice. Mechanistically, CD11b-mediated NLRP3 inflammasome activation contributes to paraquat and maneb-induced LC/NE neurodegeneration. Compared with WT controls, CD11b deficiency reduced paraquat and maneb-induced NLRP3 expression, caspase-1 activation, and interleukin-1β production in mice. Furthermore, inhibition of NLRP3 inflammasome by glybenclamide, a sulfonylurea inhibitor of NLRP3 inflammasome, was found to be able to suppress microglial proinflammatory activation and nuclear factor-κB activation induced by paraquat and maneb. Moreover, reduced reactive oxygen species production, NADPH oxidase, and inducible nitric oxide synthase expressions as well as 4-hydroxynonenal and malondialdehyde levels were detected in combined glybenclamide and paraquat and maneb-treated mice compared with paraquat and maneb alone group. Finally, we found that glybenclamide treatment ameliorated LC/NE neurodegeneration and α-synuclein aggregation in paraquat and maneb-treated mice.ConclusionOur findings suggested that CD11b mediates LC/NE neurodegeneration through NLRP3 inflammation-dependent microglial proinflammatory activation in a two pesticide-induced mouse PD model, providing a novel insight into the immune pathogenesis of LC/NE neuronal damage in related disorders.
Highlights
The loss of locus coeruleus noradrenergic (LC/NE) neurons in the brainstem is reported in multiple neurodegenerative disorders, including Parkinson’s disease (PD)
Our findings suggested that CD11b mediates LC/NE neurodegeneration through nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammationdependent microglial proinflammatory activation in a two pesticide-induced mouse PD model, providing a novel insight into the immune pathogenesis of LC/NE neuronal damage in related disorders
CD11b mediates P + M-induced LC/NE neurodegeneration in mice To determine whether CD11b contributes to LC/NE neurodegeneration in PD, we initially determined the expressions of CD11b in P + M-induced mouse PD model
Summary
The loss of locus coeruleus noradrenergic (LC/NE) neurons in the brainstem is reported in multiple neurodegenerative disorders, including Parkinson’s disease (PD). Whether CD11b is involved in LC/NE neurodegeneration in PD remains to be investigated. The degeneration of LC/NE neurons is detected in multiple neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [3, 4]. Lesion of LC/NE neurons by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a selective LC/NE neurotoxicant, exacerbates dopaminergic neurodegeneration and motor deficits in mouse PD models generated by lipopolysaccharide (LPS) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [7,8,9], highlighting its importance in the pathogenesis of PD. The mechanisms of LC/NE neurodegeneration remain unclear
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