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NLRP3 Inflammasome Pathway Is Involved in Olfactory Bulb Pathological Alteration Induced by MPTP

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NLRP3 Inflammasome Pathway Is Involved in Olfactory Bulb Pathological Alteration Induced by MPTP www.nature.com/aps ARTICLE NLRP3 inflammasome pathway is involved in olfactory bulb pathological alteration induced by MPTP Ying Chen1, Qiu-shuang Zhang1, Qian-hang Shao1, Shuo Wang1, Yu-he Yuan1, Nai-hong Chen1 and Hong-bo Wang2 Olfactory bulb, as one of sensory organs opening to the outside, is susceptible to toxic environment and easy to deteriorate. Recent studies in Parkinson’s disease (PD) patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys have shown that abnormal α-synuclein is accumulated in the olfactory glomeruli, suggesting that the lesions of PD are not only confined to the substantia nigra (SN) but also located in the olfactory bulb. Thus, olfactory bulb might be the region of onset in PD pathogenesis and a targeted region for diagnosis and treatment of PD. However, the relationship between olfactory bulb and pathogenesis of PD remains unclear. In the present study, we investigated the inflammatory pathological alterations in olfactory bulb and the underlying mechanisms in chronic MPTP mice. Mice were treated with MPTP/P, i.e., MPTP (25 mg/kg, s.c.) plus probenecid (250 mg/kg, i.p.) every 4 days, for ten times. The mice displayed typical parkinsonian syndrome. Then we examined their olfactory function and the pathologic changes in olfactory bulb. The mice showed obvious olfactory dysfunction in a buried pellet test. Immunohistochemical studies revealed that tyrosine hydroxylase (TH) protein levels were significantly decreased, whereas abnormal α-synuclein was significantly increased in the olfactory bulbs. Furthermore, the olfactory bulbs in MPTP/P-treated mice showed significantly increased levels of interleukin-1β (IL-1β), caspase-1, glial fibrillary acidic protein (GFAP), Toll receptor 4 (TLR4), phosphorylation of p65, as well as activated molecules of NOD-like receptor protein 3 (NLRP3) that were associated with neuroinflammation. Our results demonstrate that MPTP/P-caused olfactory bulb damage might be related to NLRP3-mediated inflammation. Keywords: Parkinson’s disease; olfactory bulb; α-synuclein; TLR4; NF-κB; NLRP3; neuroinflammation; MPTP; probenecid Acta Pharmacologica Sinica (2019) 40:991–998; https://doi.org/10.1038/s41401-018-0209-1 INTRODUCTION and 6-hydroxydopamine (6-OHDA) were injected into the Parkinson’s disease (PD) is a neurodegenerative disorder with a olfactory bulb in rabbits, dopamine (DA) neurons in the SN wide variety of symptoms, including motor dysfunction and and striatum were lost, verifying the ability of external toxicants nonmotor symptoms [1]. The primary pathological alterations are to accelerate PD pathogenesis and the dopaminergic projection the degeneration of dopaminergic neurons [2] and the aggrega- relationship between the SN and olfactory bulb [9]. However, tion of abnormal α-synuclein [3]; thus, PD is also called a the mechanisms underlying olfactory bulb degeneration remain proteinopathy [4]. Motor dysfunction includes bradykinesia, unknown. muscular rigidity and resting tremors [5], and nonmotor symp- Neuroinflammation is a common neuropathological finding in toms include hyposmia, constipation and other features [1]. The degenerative diseases. Studies have indicated that chronic mild pathogenesis of PD remains elusive, but investigators have come inflammation contributes to degeneration of dopaminergic to a consensus on the contribution of genetic and environmental neurons in PD [10, 11] and can increase the production of factors to the mechanisms of PD [1]. Because nonmotor symptoms reactive oxygen species (ROS), ultimately leading to neuronal precede the behavioral disorders [1], it is necessary to investigate death [12]. Many factors trigger neuroinflammation, such as ion the mechanism underlying the nonmotor symptoms. channels, microRNAs, autophagy, and monocyte activation [13]. In addition to the loss of neurons in the SN, pathological Therefore, it is essential to focus on the inflammatory process in changes also emerged in the olfactory bulb [6]. Given studies of the pathogenesis of PD. The NLRP3 inflammasome, closely related PD patients and MPTP-induced monkeys, researchers have to IL-1β production, is a multiprotein complex that plays a key role demonstrated that α-synuclein aggregation first appears in the in inflammation [14]. Hyposmia is an early symptom of PD, olfactory bulb and vagus and then spreads to the central and neuroinflammation or neuron loss also appears in the nervous system over decades [7]. Additionally, α-synuclein olfactory bulb, but the molecular mechanism underlying these monomers and oligomers can transfer from olfactory bulb to symptoms is still unknown. In this study, we investigated other brain regions through neural pathways [8]. When MPTP inflammation-related pathological alterations and the associated 1State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China and 2Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai 264005, China Correspondence: Yu-he Yuan ([email protected]) or Nai-hong Chen ([email protected]) Received: 24 October 2018 Accepted: 24 December 2018 Published online: 6 February 2019 © CPS and SIMM 2019 NLRP3 contributes to the olfactory dysfunction Y Chen et al. 992 mechanisms in the olfactory bulb induced by chronic MPTP in 0.1 mol/L NaOH, and the pH adjusted to 7.4 with Tris-HCl (pH administration in mice. 6.8). MPTP-HCl was dissolved in 0.9% saline away from light and used immediately. Model mice were administered MPTP/P every 4 days, for a total of ten doses (Fig. 1b). The mice were given an MATERIALS AND METHODS intraperitoneal injection of probenecid (250 mg/kg) and a Materials subcutaneous injection of MPTP-HCl (25 mg/kg) after 1 h. Control MPTP hydrochloride and probenecid were purchased from Sigma- group mice were treated with equal volumes of 0.9% saline via Aldrich, USA. Antibodies were obtained from Santa Cruz, Abcam, subcutaneous injection. Thermo and Wako and they are described in Table 1. Buried pellet test Animals This test was performed as described by Yan Liu et al. [15]. In a Male C57BL/6 mice (8 weeks, 22–25 g) were ordered from Vital preliminary experiment, a buried pellet test was adopted to detect River Laboratory Animal Technology Co. Ltd, Beijing, China. The the smell sensations of mice. All mice were fasted for 16–18 h with mice were raised in an experimental animal room and bred with normal access to drinking water before the test. Every mouse adapted an adequate supply of food and water. The room was managed by itself to a clean storage cage (25 cm × 15 cm × 13 cm) for 5 min and specific personnel to guarantee a 12 h light/dark cycle with a then was transferred to a test box (46 cm × 23.5 cm × 20 cm) and constant temperature of approximately 22 ± 1 °C. allowed to adapt for 2 min. A piece of ordinary laboratory food (approximately 1.0 g) was buried at a depth of 1 cm below the Experimental procedures bedding and placed on the walls of the box randomly. Each mouse Mice were randomly divided into two groups after 7 days of was placed in the middle of the test box, and then, the time needed adaptation: control and model groups. Probenecid was dissolved to find the food was recorded (the time was limited to 5 min). Table 1. The information of the antibodies used in the present work Antibody Source Dilutions Company κ 1234567890();,: NF- B/p65 Mouse 1:500 Santa Cruz Biotechnology TH Rabbit 1:500 Santa Cruz Biotechnology IL-1β Rabbit 1:500 Santa Cruz Biotechnology NLPR3 Rabbit 1:1000 Abcam Caspase-1 Mouse 1:1000 Abcam TLR4 Rabbit 1:500 Santa Cruz Biotechnology α-Synuclein(C20) nitrated Mouse 1:500 Santa Cruz Biotechnology Tyr125/Tyr133 α-synuclein Mouse 1:1000 Thermo Fisher Scientific p-p65 Rabbit 1:1000 Cell Signaling Technology β-actin Mouse 1:1000 Sigma GFAP Mouse 1:1000 Wako Fig. 1 Schematic showing the experimental design. a The neurotoxicity of MPTP triggers parkinsonism symptoms. b Schematic of the experimental procedure Acta Pharmacologica Sinica (2019) 40:991 – 998 NLRP3 contributes to the olfactory dysfunction Y Chen et al. 993 Tissue preparation antibodies for 2 h, and then visualized with an enhanced Chloral hydrate was applied to deeply anesthetize the mice (400 chemiluminescence (ECL) plus system (Molecular Device, LMAX). mg/kg, i.p.). We quickly isolated the olfactory bulb and placed the The protein bands were quantitatively analyzed using Quantity tissues into a −80 °C freezer for biochemical analysis. For One software (Toyobo, Japan). morphological observation, we perfused some of the anesthetized mice with 0.1 mol/L phosphate-buffered saline (PBS) and 4% Statistical analysis paraformaldehyde (pH 7.4, dissolved with PBS) for histologic GraphPad Prism 6.0 software (GraphPad, San Diego, CA, USA) has analysis. The olfactory bulb was kept in 4% paraformaldehyde for been widely adopted for statistical analysis. Data were analyzed 24 h to fix tissues and then dehydrated in different ethanol via t-test analysis using an unpaired t-test and were displayed as concentrations (75%–85%–90%–95%–100%). Then, the olfactory the means ± standard error (SEM). Significance was considered at bulb was embedded in paraffin, cut into slices (4 μm) and placed P < 0.05. on glass slides. Ultrastructural transmission electron microscopy (TEM) RESULTS Tissues were steeped in 4% paraformaldehyde and then cut into Olfactory dysfunction was observed in mice injected with MPTP/ cubic sections approximately 1 mm3. After being fixed with 2.5% Pro glutaraldehyde for 2 h, the sections were washed with 0.1 mol/L All mice performed the buried pellet test, and the number of mice PBS and dehydrated on a gradient. Then, we embedded the missing food in the model group was twice that in the control sections inside of Epon resin and cut them into ultrathin slices.
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