Chitotriosidase attenuates brain inflammation via HDAC3/NF-κB pathway in D-galactose and aluminum-induced rat model with cognitive impairments
Introduction
Alzheimer's disease (AD) is the most common neurodegenerative disease, whose etiology and pathogenesis are unknown (Vasefi et al., 2019). The main pathological discovery of AD contain Aβ plaques, tau tangles, synaptic degradation, and neuronal loss (Magalingam et al., 2018). Recently, microglia-associated inflammation becomes an important target in AD mechanisms. Microglia have different cellular phenotypes at different phases of the disease and play different roles in AD progression. Typically, microglia are divided into M1 type and M2 type. The former secretes TNF-α, IL-1, ROS, etc., which can promote inflammation while resulting in neurotoxic damage. The latter secretes Arg1, neurotrophic factors, etc., inhibits the inflammatory responses and promotes tissue repair (Tang and Le, 2016).
Chitotriosidase (CHIT1), located in chromosome 1q31-q32, is a member of the mammalian chitinase family and is synthesized and secreted by specifically activated macrophages/microglia (Barone et al., 2007; Olsson et al., 2012; Malaguarnera, 2006). CHIT1 was first described in plasma from patients with Gaucher disease (Hollak et al., 1994). Significant changes in CHIT1 expression were found at sites of inflammation, remodeling, and fibrosis (Pesce et al., 2006; Migliaccio et al., 2008). Increased levels of the enzyme have been detected in the cerebrospinal fluid and peripheral blood of AD patients (Di Rosa et al., 2006; Watabe-Rudolph et al., 2012). Previous research by our team has found that CHIT1 potentially plays a protective role against AD by polarizing microglia to an M2 phenotype and resisting Aβ oligomer deposition (Xiao et al., 2017). However, the signaling pathway which corresponds to the underlying mechanism of CHIT1 in AD is still unknown.
Histone deacetylase 3 (HDAC3) is a subtype of HDACs and has been found to be a critical negative regulator of long-term memory formation (McQuown et al., 2011). Inhibitors of HDACs have been shown to suppress the expression of pro-inflammatory factors such as TNF-α, IL-1β, etc., and further to improve neural function in cerebral infarction (Qi et al., 2004; Faraco et al., 2006). HDAC3-selective inhibitors demonstrate anti-inflammatory properties on macrophages by attenuating nuclear factor-kappa B (NF-κB) p65 transcriptional activity (Leus et al., 2016). Moreover, research shows that the inhibitor of HDAC3 suppresses the induction of inflammatory cytokines in rat models of acute liver failure by modulating the acetylation of NF-κB (Zhang et al., 2015). Recently, it is reported that specific inhibition of HDAC3 reversed the pathological changes of AD both in vitro and in a mouse model of AD (Janczura et al., 2018).
Considering both CHIT1 and HDAC3/NF-κB contribute to inflammation, we suspected that CHIT1 might be the upstream of HDAC3/NF-κB in AD-brain. Therefore, we designed the present study to supply the evidence that CHIT1 regulates brain inflammation via HDAC3 and NF-κB pathway.
Section snippets
Animal models
Adult male Sprague-Dawley rats (3 months old, weighing 300−320 g) were purchased from the Animal Center of Chongqing Medical University (Chongqing, China). Water and food were readily available to the rats throughout the experiment. Conditions were controlled as follows: temperature, 25 ± 1 °C; humidity, 50 ± 10 %; and light, 12-h light/dark cycle. All experiments had approval from the Experimental Animal Ethics Committee of Chongqing Medical University.
The subacute model of AD induced by D-gal
CHIT1 intervention made cognitive function of subacute AD model rats changed
In order to assess the cognitive function of rats, we performed MWM test. In the place navigation trial, the escape latency of the AD model group was considerably longer than that of the control group (p < 0.05) (Fig. 1a). In addition, the escape latency of the AD model group treated with CHIT1 was significantly shorter than that of the AD model rats (p < 0.05), while the escape latency of the AD model group treated with CHIT1 inhibitor (CHIT1-IN-2) was significantly longer than CHIT1 treatment
Discussion
In the present study, we demonstrate that CHIT1 ameliorates the cognitive impairment by modulation of brain inflammation via HDAC3/NF-κB pathway. To our knowledge, this is the first time to provide evidence that CHIT1 promote brain anti-inflammatory environment via HDAC3/NF-κB signaling.
Our previous study indicates that CHIT1 provides potential protection through microglial polarization and reduction of Aβ oligomers in D-gal and AlCl3-induced rat model with cognitive impairments (Xiao et al.,
Conclusions
In conclusion, our study indicates that CHIT1 reduces brain inflammation the HDAC3/NF-κB p65 pathway in AD, and this study also highlights the importance of epigenetics in AD. In addition, our experiment also helped to elucidate the mechanism of action of CHIT1.
Author contributions
Xingyan Yu and Yang Lü designed the experiments. Xingyan Yu, Weihua Yu, Lihua Wu and Wenkai Yang performed the experiments and analyzed all data. Xingyan Yu drafted the manuscript. Yang Lü revised the manuscript.
Funding
This study was supported by grants from Chongqing Natural Science Foundation (cstc2018jcyjAX0169).
Declaration of Competing Interest
The authors report no declarations of interest.
References (38)
- et al.
Histone deacetylase 3 suppression increases PH domain and leucine-rich repeat phosphatase (Phlpp)1 expression in chondrocytes to suppress Akt signaling and matrix secretion
J. Biol. Chem.
(2013) - et al.
d-galactose and aluminium chloride induced rat model with cognitive impairments
Biomed. Pharmacother.
(2018) - et al.
Inflammation as a central mechanism in Alzheimer’s disease
Alzheimers Dement (N Y)
(2018) - et al.
HDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-kappaB p65 transcriptional activity
Biochem. Pharmacol.
(2016) - et al.
Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway
J. Biol. Chem.
(2004) - et al.
Acetylation of non-histone proteins modulates cellular signalling at multiple levels
Int. J. Biochem. Cell Biol.
(2009) - et al.
Chitotriosidase enhances TGFbeta-Smad signaling and uptake of beta-amyloid in N9 microglia
Neurosci. Lett.
(2018) - et al.
Chitinase1 contributed to a potential protection via microglia polarization and Abeta oligomer reduction in D-galactose and aluminum-induced rat model with cognitive impairments
Neuroscience
(2017) - et al.
Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice
Am. J. Pathol.
(2007) - et al.
Plasma chitotriosidase in health and pathology
Clin. Lab.
(2007)
Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages
Proc. Natl. Acad. Sci. U. S. A.
Centella asiatica protects d-galactose/AlCl3 mediated Alzheimer’s disease-like rats via PP2A/GSK-3β signaling pathway in their hippocampus
Int. J. Mol. Sci.
Rhinacanthin C alleviates Amyloid-β fibrils’ toxicity on neurons and attenuates neuroinflammation triggered by LPS, Amyloid-β, and Interferon-γ in glial cells
Oxid. Med. Cell. Longev.
Microglia mediated neuroinflammation: focus on PI3K modulation
Biomolecules
Gastrodin inhibits expression of inducible NO synthase, cyclooxygenase-2 and proinflammatory cytokines in cultured LPS-stimulated microglia via MAPK Pathways
PLoS One
Chitotriosidase and inflammatory mediator levels in Alzheimer’s disease and cerebrovascular dementia
Eur. J. Neurosci.
Current insights into the regulation of programmed cell death by NF-kappaB
Oncogene
Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain
Mol. Pharmacol.
Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease
J. Clin. Invest.
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