Editor’s Highlight: Nlrp3 Is Required for Inflammatory Changes and Nigral Cell Loss Resulting From Chronic Intragastric Rotenone Exposure in Mice

Abstract

Complex interactions between genetic and environmental factors are widely believed to underlie the incidence and progression of Parkinson's disease (PD). Rotenone is a naturally occurring metabolic toxin employed as an insecticide and piscicide identified as a risk factor for the development of PD in agricultural workers. The Nlrp3 inflammasome is an intracellular mediator that can initiate an inflammatory cascade in response to cellular stress. Reports by others indicating that NLRP3 expression was detectable in tissues obtained from Alzheimer's disease patients and that the PD-associated protein α-synuclein could activate inflammasomes in cultured glial cells, prompted us to test the prediction that Nlrp3 was required for the development of Parkinson's-like changes resulting from rotenone exposure in mice. We exposed wild type and Nlrp3-/- mice to chronic low doses of intragastric rotenone and conducted longitudinal behavioral and serum cytokine analysis followed by evaluation of neuroinflammatory and neurodegenerative endpoints in brain tissues. We observed progressive rotenone-dependent changes in serum cytokine levels and circulating leukocytes in wild type mice not observed in Nlrp3-/- mice. Analysis of brain tissues revealed Nlrp3-dependent neuroinflammation and nigral cell loss in mice exposed to rotenone as compared with mice exposed to vehicle alone. Together, our findings provide compelling evidence of a role for Nlrp3 in nigral degeneration and neuroinflammation resulting from systemic rotenone exposure and suggest that the suppression of NLRP3 activity may be a rational neuroprotective strategy for toxin-associated PD.

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice

“…Our studies have been consistent with these reports [14], however, we also unexpectedly identified NLRP3 expression in a subset of surviving DA neurons in late stage PD patients and neuronal cell models [40]. Others report inflammasome activity in neurons [27, [49][50][51], but to our knowledge no in vivo studies have examined directly the function of NLRP3 in DA neurons in the context of aging.…”

“…In addition to observing an increased number of GFAP-immunoreactive astrocytes associated with aging, we also observed significantly more astroglia in 18-month old animals expressing Nlrp3 L351P compared to animals expressing Nlrp3 WT and Nlrp3 A350V . We and others have previously reported astrocytes to be a direct target of IL-1b [14,[59][60][61] the canonical proinflammatory effector cytokine of the inflammasome [7], and others have previously reported evidence of neuronal IL-1b expression [62]. Analysis of SNpC tissues was consistent with these previous reports, demonstrating easily observable IL-1b expression in TH-immunoreactive fibers ( Supplementary Figure 2).…”

“…The NLRP3 inflammasome is of particular interest in neurologic disorders because it can be activated by sterile cellular stressors common to many neurodegenerative diseases including proteinaceous insult [35], oxidative stress [36,37], environmental toxicants [38], and cell death [39]. Characterizing NLRP3 in Parkinson's disease (PD), we observed NLRP3 inflammasome activity in PD patients [40] and demonstrated that loss of Nlrp3 is neuroprotective in a toxicant-based mouse model of PD [14].…”

“…Inflammasomes are widely accepted to be key mediators of the innate immune response with many studies characterizing their activities in hematopoietic cells of the myeloid lineage, and more recent studies by our laboratory [14] and others [15][16][17][18][19] characterizing NLRP3 inflammasome activity in functionally related microglia of the central nervous system (CNS).…”

Submicron Crystals of the Parkinson’s Disease Substantia nigra: Calcium Oxalate, Titanium Dioxide and Iron Oxide

“…Studies of the past 5 years have shown that a cause of the degeneration is inflammatory attack of dopaminergic neurons of the substantia nigra by microglia when their NLRP3 inflammasome is activated by phagocytized misfolded α-synuclein. [1][2][3][4][5][6][7][8][9][10][11][12] The misfolded β-sheet-rich α-synuclein aggregates in PD's hallmark Lewy bodies. If misfolded α-synuclein templates the misfolding of more synuclein, it constitutes a PD-propagating prion.…”