Inhibition of the hepatic Nlrp3 protects dopaminergic neurons via attenuating systemic inflammation in a MPTP/p mouse model of Parkinson’s disease

Abstract

BackgroundParkinson’s disease (PD) is a neurodegenerative disorder with progressive loss of dopaminergic (DA) neurons. Systemic inflammation is shown to initiate and exacerbate DA neuronal degeneration in the substantia nigra. The infiltration and transformation of immune cells from the peripheral tissues are detected in and around the affected brain regions of PD patients. Our previous studies demonstrated the crucial role that microglial Nod-like receptor protein (NLRP) 3 inflammasome plays in the pathogenesis of PD. Nevertheless, the direct linkage between peripheral inflammation and DA neuron death remains obscure.MethodsIn the present study, we detected the NLRP3 expressions in the midbrain, liver, and bone marrow-derived macrophages in response to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) acute and chronic challenge. We then used a tail vein injection of Nlrp3-siRNA wrapped with lentivirus to explore the potential influence of hepatic NLRP3 inflammasome-mediated inflammation on neuronal injury in a mouse model of PD via immunohistochemistry, ELISA, and Western blotting analysis.ResultsWe showed that siNlrp3 downregulated the NLRP3 protein expression and inhibited the activation of NLRP3 inflammasomes in mice livers. The tail vein injection of LV3-siNlrp3 reduced the liver pro-inflammatory cytokine production, which subsequently alleviated MPTP-triggered microglial activation and DA neuron loss in the midbrain. These findings indicated that inhibition of hepatic NLRP3 inflammasome weakens inflammatory cytokines spreading into the brain and delays the progress of neuroinflammation and DA neuronal degeneration.ConclusionThis study gives us an insight into the direct linkage between liver inflammation and DA neuron damage in the pathogenesis of PD and provides the potential target of NLRP3 for developing novel drugs for PD therapy.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1236-z) contains supplementary material, which is available to authorized users.

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

“…59 A study also established a link between peripheral inflammation and dopaminergic neuronal loss. 60 Mice injected with lentivirus-wrapped siNlrp3 reduced hepatic inflammasome-mediated cytokine release and prevented it from crossing the BBB and progression of neuroinflammation and damage to DA neurons. 60 α-Synuclein Activates the NLRP3 Inflammasome.…”

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

“…In mice, activation of microglial NLRP3 inflammasome by misfolded α-synuclein causes the death of proximal dopaminergic neurons. [1,3,[8][9][10][11] The found TiO2 particles are coated with a protein-layer, constituting about 20 % of their mass. TiO2, shown to adsorb and orient peptides and polymers [27][28][29] could also adsorb α-synuclein or its precursor peptides.…”

“…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.…”

Neurodegenerative Susceptibility During Maternal Nutritional Programing: Are Central and Peripheral Innate Immune Training Relevant?

“…Potential molecular mechanisms that regulate peripheral immune training linked to NLRP3 inflammasome and neurodegeneration are being elucidated. Qiao et al (2018) identified that hepatic NLRP3 inflammasome inhibition by in vivo siRNA administration decreases the TNF-α, IL-β, IL-12, and IL-18 serum levels. Of note, inhibition of the hepatic NLRP3 inflammasome partially prevents dopaminergic neuronal death in the substantia nigra of a murine Parkinson model by decreasing the pro-inflammatory profile in plasma (Qiao et al, 2018).…”

“…Qiao et al (2018) identified that hepatic NLRP3 inflammasome inhibition by in vivo siRNA administration decreases the TNF-α, IL-β, IL-12, and IL-18 serum levels. Of note, inhibition of the hepatic NLRP3 inflammasome partially prevents dopaminergic neuronal death in the substantia nigra of a murine Parkinson model by decreasing the pro-inflammatory profile in plasma (Qiao et al, 2018). It seems that immune activation, at least for viral infections, depends on CXCR6, a chemokine receptor of hepatic NK cells involved in the persistence of cellular memory (Netea et al, 2011).…”