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.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder with progressive loss of dopaminergic (DA) neurons
The expressions of NLRP1 and nod-like receptor protein 3 (NLRP3) were upregulated, in acute MPTP model, and in chronic MPTP/p model, without changes in other inflammasomes (T test, p < 0.001). These results suggested that the NLRP1 and the NLRP3 inflammasome activation could be involved in the pathogenesis of PD
The results found that the reduction of NLRP3 in the liver could decrease the release of pro-inflammatory cytokines from the liver into serum and brain, even inhibiting MPTP-induced microglia activation and DA neuron loss in the mouse substantia nigra pars compacta (SNc), without affecting the metabolism of MPTP
Summary
Parkinson’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. Parkinson’s disease (PD) is a common age-related neurodegenerative disease that is induced by multitudinous environmental and inherited factors [1]. PD is characterized by the progress degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc), as. Most researches have focused on the neuroinflammation process of PD, while systemic inflammatory responses, especially peripheral inflammation acts as an inescapable risk factor during the pathological process of PD [7, 8]. The infiltration of peripheral inflammatory cytokines and immune cells permeate through the BBB to induce the degeneration of dopaminergic neurons in the SNc [10]. The ability to reduce or control the systemic inflammatory response has important significance in developing novel anti-inflammatory medicines for PD therapy
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