Small molecule-driven NLRP3 inflammation inhibition via interplay between ubiquitination and autophagy: implications for Parkinson disease

Abstract

Aging-related, nonresolving inflammation in both the central nervous system (CNS) and periphery predisposes individuals to the development of neurodegenerative disorders (NDDs). Inflammasomes are thought to be especially relevant to immune homeostasis, and their dysregulation contributes to inflammation and NDDs. However, few agents have been clinically shown to reduce NDD incidence by targeting inflammasomes. Our study indicated that NLRP3 (NLR family, pyrin domain containing 3) inflammasome is involved in Parkinson disease (PD) progression in patients and various murine models. In addition, the small molecule kaempferol (Ka) protected mice against LPS-and SNCA-induced neurodegeneration by inhibiting NLRP3 inflammasome activation as evidenced by the fact that Ka reduced cleaved CASP1 expression and disrupted NLRP3-PYCARD-CASP1 complex assembly with concomitant decreased IL1B secretion. Mechanically, Ka promoted macroautophagy/autophagy in microglia, leading to reduced NLRP3 protein expression, which in turn deactivated the NLRP3 inflammasome. Intriguingly, ubiquitination was involved in Ka-induced autophagic NLRP3 degradation. These findings were further confirmed in vivo as knockdown of Atg5 expression or autophagy inhibitor treatment significantly inhibited the Ka-mediated NLRP3 inflammasome inhibition and neurodegeneration amelioration. Thus, we demonstrated that Ka promotes neuroinflammatory inhibition via the cooperation of ubiquitination and autophagy, suggesting that Ka is a promising therapeutic strategy for the treatment of NDDs.

Only IL‐1β release is inflammasome‐dependent upon ultraviolet B irradiation although IL‐18 is also secreted

“…Additionally, our observation that inflammasome‐related cytokines IL‐1β and IL‐18 have distinct signaling pathways upon same activator affords novel information to understand better the inflammasome signaling also in other than RPE cells. Therefore, our findings can be utilized in research of various chronic diseases, where inflammasomes are involved in the disease progression, for example, Alzheimer's disease and Parkinson's disease 57‐59 …”

URB597 protects against NLRP3 inflammasome activation by inhibiting autophagy dysfunction in a rat model of chronic cerebral hypoperfusion

“…In our previous studies [9,11], we found that CCH caused the release of proinflammatory cytokines and induced lysosomal dysfunction, which may promote the accumulation of autophagosomes, resulting in abnormal excessive autophagy. Since it has been reported that autophagy dysfunction may contribute to the induction of neuroinflammation [29,30], we examined whether there was a link between abnormal excessive autophagy and neuroinflammation in the presence of CCH. We investigated the expression of inflammatory markers, including TNF-α, IL-1β, COX-2 and iNOS, in the hippocampus.…”

Opposing functions of β-arrestin 1 and 2 in Parkinson’s disease via microglia inflammation and Nprl3

“…The LPS-and MPTP-induced PD models were developed as described previously [36,37]. Brie y, mice (male, 3-4 months old, n = 11 for each genotype) were microinjected bilaterally with LPS (0.5 µg in 1 µl of saline, Sigma) at the SNc (AP: -3.0 mm; ML: ± 1.3 mm; DV: -4.2 mm) at a rate of 0.2 µl/min in a stereotaxic apparatus or administered with MPTP (20 mg/kg, i.p., Sigma) 4 times at 2-h intervals.…”

“…Frozen 30-µm-thick midbrain sections or primary DA neurons were depara nized by treatment with 3% H 2 O 2 for 30 min, blocked by 5% BSA plus 0.3% Triton X-100 for 60 min, and then incubated with anti-TH (1:1000) or anti-Iba-1(1:1000) antibodies at 4 °C overnight as described [37]. After washing, the slides were incubated with secondary antibodies (1:1000) for 60 min.…”