Toll-like receptors and NLRP3 inflammasome-dependent pathways in Parkinson's disease: mechanisms and therapeutic implications

Abstract

Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder characterized by motor and non-motor disturbances as a result of a complex and not fully understood pathogenesis, probably including neuroinflammation, oxidative stress, and formation of alpha-synuclein (α-syn) aggregates. As age is the main risk factor for several neurodegenerative disorders including PD, progressive aging of the immune system leading to inflammaging and immunosenescence may contribute to neuroinflammation leading to PD onset and progression; abnormal α-syn aggregation in the context of immune dysfunction may favor activation of nucleotide-binding oligomerization domain-like receptor (NOD) family pyrin domain containing 3 (NLRP3) inflammasome within microglial cells through interaction with toll-like receptors (TLRs). This process would further lead to activation of Caspase (Cas)-1, and increased production of pro-inflammatory cytokines (PC), with subsequent impairment of mitochondria and damage to dopaminergic neurons. All these phenomena are mediated by the translocation of nuclear factor kappa-B (NF-κB) and enhanced by reactive oxygen species (ROS). To date, drugs to treat PD are mainly aimed at relieving clinical symptoms and there are no disease-modifying options to reverse or stop disease progression. This review outlines the role of the TLR/NLRP3/Cas-1 pathway in PD-related immune dysfunction, also focusing on specific therapeutic options that might be used since the early stages of the disease to counteract neuroinflammation and immune dysfunction.

Keywords: Inflammation; Innate immunity; Parkinson’s disease; TLR/NLRP3/Caspase-1 pathway; Toll-like receptors; α-synuclein.

Fig. 1

A two-signal model for NLRP3 inflammasome activation. A bimodal signaling pathway is required to induce the NLRP3 inflammasome activation: the TLR-dependent priming signal (signal 1) is provided by alpha-syn or endogenous cytokines, and leads to the activation of the transcription factor NF-kB and subsequent up-regulation of NLRP3 and pro-interleukin-1β (pro-IL-1β); NLRP3 undergoes post-translational modifications that license its activation. The activation signal (signal 2), provided by a variety of stimuli and multiple molecular or cellular events, including ionic flux, mitochondrial dysfunction with ROS generation, and lysosomal damage, activates the NLRP3 inflammasome, with subsequent activation (cleavage) of Caspase-1, that in turn catalyzes the cleavage of IL-1β and IL-18. The NLRP3 inflammasome may also be activated by agents that cause mitochondrial dysfunction, leading to generation of mitochondrial ROS. IL-1beta-R IL-1β receptor, TLR toll-like receptor, alpha-syn alpha-synuclein, ROS reactive oxygen species