Porphyromonas Gingivalis Infection Induces Synaptic Failure via Increased IL-1β Production in Leptomeningeal Cells

2021 ◽  
pp. 1-17
Author(s):  
Wanyi Huang ◽  
Fan Zeng ◽  
Yebo Gu ◽  
Muzhou Jiang ◽  
Xinwen Zhang ◽  
...  
Keyword(s):  
Porphyromonas Gingivalis ◽  
Nlrp3 Inflammasome ◽  
Cortical Neurons ◽  
Inflammasome Activation ◽  
Memory Decline ◽  
Periodontal Bacteria ◽  
Nlrp3 Inflammasome Activation ◽  
Synaptic Failure ◽  
Pre Treatment ◽  
The Impact

Background: Studies have reported that synaptic failure occurs before the Alzheimer’s disease (AD) onset. The systemic Porphyromonas gingivalis (P. gingivalis) infection is involved in memory decline. We previously showed that leptomeningeal cells, covering the brain, activate glial cells by releasing IL-1β in response to systemic inflammation. Objective: In the present study, we focused on the impact of leptomeningeal cells on neurons during systemic P. gingivalis infection. Methods: The responses of leptomeningeal cells and cortical neurons to systemic P. gingivalis infection were examined in 15-month-old mice. The mechanism of IL-1β production by P. gingivalis infected leptomeningeal cells was examined, and primary cortical neurons were treated with P. gingivalis infected leptomeningeal cells condition medium (Pg LCM). Results: Systemic P. gingivalis infection increased the expression of IL-1β in leptomeninges and reduced the synaptophysin (SYP) expression in leptomeninges proximity cortex in mice. Leptomeningeal cells phagocytosed P. gingivalis resulting in lysosomal rupture and Cathepsin B (CatB) leakage. Leaked CatB mediated NLRP3 inflammasome activation inducing IL-1β secretion in leptomeningeal cells. Pg LCM decreased the expression of synaptic molecules, including SYP, which was inhibited by an IL-1 receptor antagonist pre-treatment. Conclusion: These observations demonstrate that P. gingivalis infection is involved in synaptic failure by inducing CatB/NLRP3 inflammasome-mediated IL-1β production in leptomeningeal cells. The periodontal bacteria-induced synaptic damage may accelerate the onset and cognitive decline of AD.

scholarly journals Leptomeningeal cells induce synaptic failure via Cathepsin B-mediated IL-1β production after Porphyromonas gingivalis infection

2020 ◽  
Author(s):  
Wanyi Huang ◽  
Fan Zeng ◽  
Yebo Gu ◽  
Muzhou Jiang ◽  
Xinwen Zhang ◽  
...  
Keyword(s):  
Porphyromonas Gingivalis ◽  
Nlrp3 Inflammasome ◽  
Cortical Neurons ◽  
Cathepsin B ◽  
Immunofluorescent Staining ◽  
Inflammasome Activation ◽  
Primary Cortical Neurons ◽  
Memory Decline ◽  
Synaptic Failure ◽  
Bdnf Signaling

Abstract Background: Synaptic failure is the earliest sign before Alzheimer’s disease (AD) onset and closely associated with cognitive decline. Clinical studies have shown that periodontitis is positively correlated with both the onset and progression of AD, and preclinical studies have shown that Porphyromonas gingivalis (P. gingivalis) and its virulence factors induced memory decline in mice. However, the mechanisms underlying the involvement of P. gingivalis in memory decline remain unclear.Methods: Fifteen-month-old female C57/BL6J mice were intraperitoneally injected with P. gingivalislearning and memory were evaluated by step through passive avoidance tests. Immunofluorescent staining was used to examine the expression of IL-1β and synaptic markers. Primary leptomeningeal cells and primary cortical neurons were used to evaluate the its effects on synaptic generation and plasticity. The expression of related molecules was examined by Q-PCR and Western blotting. Pharmacological and genetic approaches were used to explore the roles of leptomeningeal cells in synaptic changes after P. gingivalis infection. Results: P. gingivalis infection induced the increased expression of IL-1β in leptomeninges and decreased expression of synaptophysin (SYP) in the cortex proximity of the leptomeninges, which was accompanied by memory decline in middle-aged mice. NLRP3 inflammasome activation was involved in augmenting the IL-1β secretion by primary leptomeningeal cells after P. gingivalis infection. Cathepsin B (CatB) mediated the activation of both NLRP3 inflammasome and NF-κB in P. gingivalis-infected primary leptomeningeal cells. In contrast, P. gingivalis-infected leptomeningeal cells induced an IL-1β-dependent decrease in pre- and post-synaptic molecules in primary cortical neurons, as determined by the pharmacological blockage of the IL-1 receptor. P. gingivalis-infected leptomeningeal cells also induced the IL-1β-dependent suppression of BDNF signaling in cultured N2a neurons. Furthermore, propolis produced by honeybees, suppressed the expression of IL-1β but increased that of BDNF in P. gingivalis-infected leptomeningeal cells. Conclusion: The CatB-mediated IL-1β production was augmented in leptomeningeal cells, resulting in synaptic failure and blockage of BDNF signaling in neurons during P. gingivalis infection. These findings highlight a new mechanism underlying the involvement of periodontitis in AD initiation and suggest that CatB may be an early intervention therapeutic target for delaying the onset of AD during P. gingivalis infection.

scholarly journals Leptomeningeal Cells Induce Synaptic Failure via Cathepsin B-mediated IL-1ß Production after Porphyromonas Gingivalis Infection

2020 ◽  
Author(s):  
Wanyi Huang ◽  
Fan Zeng ◽  
Yebo Gu ◽  
Muzhou Jiang ◽  
Xinwen Zhang ◽  
...  
Keyword(s):  
Porphyromonas Gingivalis ◽  
Cortical Neurons ◽  
Cathepsin B ◽  
Inflammasome Activation ◽  
Primary Cortical Neurons ◽  
Memory Decline ◽  
Protein Levels ◽  
Synaptic Failure ◽  
Bdnf Signaling

Abstract Background: Synaptic failure is the earliest sign before Alzheimer’s disease (AD) onset and closely associated with cognitive decline. Clinical studies have shown that periodontitis is positively correlated with both the onset and pathological progression of AD, and preclinical studies have shown that Porphyromonas gingivalis (P. gingivalis), the key pathogen in periodontitis, and its virulence factors induced memory decline in mice. However, the mechanisms underlying the involvement of P. gingivalis in memory decline remain unclear. Methods: We used primary leptomeningeal cells and primary cortical neurons to evaluate the effects of leptomeningeal cells on synaptic generation and plasticity after P. gingivalis infection in vitro. The expression of the related molecules was examined by mRNA in real time and by protein levels using Western blotting. Pharmacological and genetic approaches were used to explore the mechanism underlying the involvement of leptomeningeal cells in synaptic changes after P. gingivalis infection. Results: NLRP3 inflammasome activation was involved in augmenting the IL-1β secretion by primary leptomeningeal cells after P. gingivalis infection, as determined by the knockdown of NLRP3 with siRNA. Cathepsin B (CatB) mediated the activation of both NLRP3 inflammasomes and NF-κB for the production of IL-1β by P. gingivalis-infected primary leptomeningeal cells, as determined by the pharmacologically specific inhibition of CatB. In contrast, P. gingivalis-infected leptomeningeal cells induced an IL-1β-dependent decrease in pre- and post-synaptic molecules in primary cortical neurons, as determined by the pharmacological blockage of the IL-1 receptor. P. gingivalis-infected leptomeningeal cells also induced the IL-1β-dependent suppression of BDNF signaling in cultured N2a neurons, a stable mouse neural cell line. Furthermore, propolis, which is produced by honeybees, suppressed the expression of IL-1β but increased that of BDNF in P. gingivalis-infected leptomeningeal cells. Conclusion: The CatB-mediated IL-1β production was augmented in leptomeningeal cells, resulting in synaptic failure and blockage of BDNF signaling in neurons during P. gingivalis infection. These findings highlight a new mechanism underlying the involvement of periodontitis in AD initiation and suggest that CatB may be an early intervention therapeutic target for delaying the onset of AD during P. gingivalis infection.

scholarly journals Leptomeningeal Cells Induce Synaptic Failure via Cathepsin B-mediated IL-1ß Production after Porphyromonas Gingivalis Infection

2020 ◽  
Author(s):  
Wanyi Huang ◽  
Fan Zeng ◽  
Yebo Gu ◽  
Muzhou Jiang ◽  
Xinwen Zhang ◽  
...  
Keyword(s):  
Porphyromonas Gingivalis ◽  
Cortical Neurons ◽  
Cathepsin B ◽  
Inflammasome Activation ◽  
Primary Cortical Neurons ◽  
Memory Decline ◽  
Protein Levels ◽  
Synaptic Failure ◽  
Bdnf Signaling

Abstract Background: Synaptic failure is the earliest sign before Alzheimer’s disease (AD) onset and closely associated with cognitive decline. Clinical studies have shown that periodontitis is positively correlated with both the onset and pathological progression of AD, and preclinical studies have shown that Porphyromonas gingivalis (P. gingivalis), the key pathogen in periodontitis, and its virulence factors induced memory decline in mice. However, the mechanisms underlying the involvement of P. gingivalis in memory decline remain unclear. Methods: We used primary leptomeningeal cells and primary cortical neurons to evaluate the effects of leptomeningeal cells on synaptic generation and plasticity after P. gingivalis infection in vitro. The expression of the related molecules was examined by mRNA in real time and by protein levels using Western blotting. Pharmacological and genetic approaches were used to explore the mechanism underlying the involvement of leptomeningeal cells in synaptic changes after P. gingivalis infection. Results: NLRP3 inflammasome activation was involved in augmenting the IL-1β secretion by primary leptomeningeal cells after P. gingivalis infection, as determined by the knockdown of NLRP3 with siRNA. Cathepsin B (CatB) mediated the activation of both NLRP3 inflammasomes and NF-κB for the production of IL-1β by P. gingivalis-infected primary leptomeningeal cells, as determined by the pharmacologically specific inhibition of CatB. In contrast, P. gingivalis-infected leptomeningeal cells induced an IL-1β-dependent decrease in pre- and post-synaptic molecules in primary cortical neurons, as determined by the pharmacological blockage of the IL-1 receptor. P. gingivalis-infected leptomeningeal cells also induced the IL-1β-dependent suppression of BDNF signaling in cultured N2a neurons, a stable mouse neural cell line. Furthermore, propolis, which is produced by honeybees, suppressed the expression of IL-1β but increased that of BDNF in P. gingivalis-infected leptomeningeal cells. Conclusion: The CatB-mediated IL-1β production was augmented in leptomeningeal cells, resulting in synaptic failure and blockage of BDNF signaling in neurons during P. gingivalis infection. These findings highlight a new mechanism underlying the involvement of periodontitis in AD initiation and suggest that CatB may be an early intervention therapeutic target for delaying the onset of AD during P. gingivalis infection.

scholarly journals Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

2020 ◽  
Vol 21 (11) ◽  
pp. 3740 ◽  
Author(s):  
Claudia Espinosa-Garcia ◽  
Fahim Atif ◽  
Seema Yousuf ◽  
Iqbal Sayeed ◽  
Gretchen N. Neigh ◽  
...  
Keyword(s):  
Brain Injury ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Global Ischemia ◽  
Inflammasome Activation ◽  
Ischemic Brain Injury ◽  
Primary Microglia ◽  
Ischemic Brain ◽  
Nlrp3 Inflammasome Activation ◽  
The Impact

NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3 inflammasome and autophagic response to ischemia remains unknown. Progesterone (PROG), a neuroprotective steroid, shows promise in reducing excessive inflammation associated with poor outcome in ischemic brain injury patients with comorbid conditions, including elevated stress. Stress primes microglia, mainly by the release of alarmins such as high-mobility group box-1 (HMGB1). HMGB1 activates the NLRP3 inflammasome, resulting in pro-inflammatory interleukin (IL)-1β production. In experiment 1, adult male Sprague-Dawley rats were exposed to social defeat stress for 8 days and then subjected to global ischemia by the 4-vessel occlusion model, a clinically relevant brain injury associated with cardiac arrest. PROG was administered 2 and 6 h after occlusion and then daily for 7 days. Animals were killed at 7 or 14 days post-ischemia. Here, we show that stress and global ischemia exert a synergistic effect in HMGB1 release, resulting in exacerbation of NLRP3 inflammasome activation and autophagy impairment in the hippocampus of ischemic animals. In experiment 2, an in vitro inflammasome assay, primary microglia isolated from neonatal brain tissue, were primed with lipopolysaccharide (LPS) and stimulated with adenosine triphosphate (ATP), displaying impaired autophagy and increased IL-1β production. In experiment 3, hippocampal microglia isolated from stressed and unstressed animals, were stimulated ex vivo with LPS, exhibiting similar changes than primary microglia. Treatment with PROG reduced HMGB1 release and NLRP3 inflammasome activation, and enhanced autophagy in stressed and unstressed ischemic animals. Pre-treatment with an autophagy inhibitor blocked Progesterone’s (PROG’s) beneficial effects in microglia. Our data suggest that modulation of microglial priming is one of the molecular mechanisms by which PROG ameliorates ischemic brain injury under stressful conditions.

scholarly journals Annexin-A1 tripeptide attenuates surgery-induced neuroinflammation and memory deficits through regulation of the NLRP3 inflammasome

2020 ◽  
Author(s):  
Zhiquan Zhang ◽  
Qing Ma ◽  
Ravikanth Velagapudi ◽  
William E. Barclay ◽  
Ramona M. Rodriguiz ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Morphological Changes ◽  
Memory Deficits ◽  
Inflammasome Activation ◽  
Surgical Trauma ◽  
Annexin A1 ◽  
Neuroprotective Effects ◽  
Nlrp3 Inflammasome Activation ◽  
The Impact

AbstractNeuroinflammation is a growing hallmark of perioperative neurocognitive disorders (PNDs), including delirium and longer-lasting cognitive deficits. We have developed a clinically-relevant orthopedic mouse model to study the impact of a common surgical procedure on the vulnerable brain. The mechanism underlying PNDs remain unknown. Here we evaluated the impact of surgical trauma on the NLRP3 inflammasome signaling, including the expression of apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, and IL-1β in the hippocampus of C57BL6/J male mice, adult (3-months) and aged (>18-months). Surgery triggered ASC specks formation in CA1 hippocampal microglia, but without inducing significant morphological changes in NLRP3 and ASC knockout mice. Since no therapies are currently available to treat PNDs, we assessed the neuroprotective effects of a biomimetic peptide derived from the endogenous inflammation-ending molecule, Annexin-A1 (ANXA1). We tested the hypothesis that this peptide (ANXA1sp) inhibits NLRP3 inflammasome activation, thus preventing microglial activation and hippocampal-dependent memory deficits. Together these results uncover a previously underrecognized role of the NLRP3 inflammasome in triggering postoperative neuroinflammation and offer a new target for advancing treatment of PNDs through resolution of inflammation.

scholarly journals NLRP3 inflammasome activation in aged macrophages is diminished during Streptococcus pneumoniae infection

2018 ◽  
Vol 314 (3) ◽  
pp. L372-L387 ◽  
Author(s):  
Soo Jung Cho ◽  
Kristen Rooney ◽  
Augustine M. K. Choi ◽  
Heather W. Stout-Delgado
Keyword(s):  
Streptococcus Pneumoniae ◽  
Nlrp3 Inflammasome ◽  
The United States ◽  
Biological Aging ◽  
Inflammasome Activation ◽  
Pneumococcal Infections ◽  
Nlrp3 Inflammasome Activation ◽  
The Impact

Pneumococcal infections are the eigth leading cause of death in the United States, and it is estimated that older patients (≥65 yr of age) account for the most serious cases. The goal of our current study is to understand the impact of biological aging on innate immune responses to Streptococcus pneumoniae, a causative agent of bacterial pneumonia. With the use of in vitro and in vivo aged murine models, our findings demonstrate that age-enhanced unfolded protein responses (UPRs) contribute to diminished inflammasome assembly and activation during S. pneumoniae infection. Pretreatment of aged mice with endoplasmic reticulum chaperone and the stress-reducing agent tauroursodeoxycholic acid (TUDCA) decreased mortality in aged hosts that was associated with increased NLRP3 inflammasome activation, improved pathogen clearance, and decreased pneumonitis during infection. Taken together, our data provide new evidence as to why older persons are more susceptible to S. pneumoniae and provide a possible therapeutic target to decrease morbidity and mortality in this population.

scholarly journals Ethyl Pyruvate Attenuates Microglial NLRP3 Inflammasome Activation via Inhibition of HMGB1/NF-κB/miR-223 Signaling

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 745
Author(s):  
Melis Olcum ◽  
Kemal Ugur Tufekci ◽  
Devrim Yagmur Durur ◽  
Bora Tastan ◽  
Irem Nur Gokbayrak ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Ethyl Pyruvate ◽  
Metabolic Effects ◽  
Inflammasome Activation ◽  
Neuroprotective Effects ◽  
Cellular Models ◽  
Nlrp3 Inflammasome Activation ◽  
Parkinson’S Diseases ◽  
Anti Inflammatory ◽  
The Impact

Ethyl pyruvate is a molecule with anti-inflammatory and pro-metabolic effects. Ethyl pyruvate has been shown to ameliorate the clinical and pathological findings of neurodegenerative diseases such as Alzheimer’s and Parkinson’s Diseases in rodents. Its anti-inflammatory and neuroprotective effects are widely investigated in animal and cellular models. Our study aimed to investigate the mechanism of the impact of Ethyl pyruvate on NLRP3 inflammasome activation in the N9 microglial cell line. Our results indicated that ethyl pyruvate significantly suppressed LPS and ATP-induced NLRP3 inflammasome activation, decreased active caspase-1 level, secretion of IL-1β and IL-18 cytokines, and reduced the level of pyroptotic cell death resulting from inflammasome activation. Furthermore, ethyl pyruvate reduced the formation of total and mitochondrial ROS and suppressed inflammasome-induced HMGB1 upregulation and nuclear NF-κB translocation and reversed the inflammasome activation-induced miRNA expression profile for miR-223 in N9 cells. Our study suggests that ethyl pyruvate effectively suppresses the NLRP3 inflammasome activation in microglial cells regulation by miR-223 and NF-κB/HMGB1 axis.

scholarly journals Lycopus lucidus Turcz exerts neuroprotective effect against H2O2‑induced neuroinflammation by inhibiting NLRP3 inflammasome activation in cortical neurons

2021 ◽  
Author(s):  
Hyunseong Kim ◽  
Jin Young Hong ◽  
Wan-Jin Jeon ◽  
Junseon Lee ◽  
Seung Ho Baek ◽  
...  
Keyword(s):  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Cortical Neurons ◽  
Neuronal Damage ◽  
Neuroprotective Effect ◽  
Synaptic Connectivity ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Rat Cortical Neurons

Abstract Background Central nervous system (CNS) injuries are a leading cause of permanent functional impairment in humans. Nerve damage can be aggravated by neuroinflammation mediated by protein complexes known as inflammasomes, such as the NLRP3 inflammasome which is a key mediator of caspase-1 and interleukin-1β (IL-1β) /interleukin-18 (IL-18) activation. Lycopus lucidus Turcz (LLT) is a traditional medicinal herb that exerts therapeutic effects against oxidative stress, inflammation, and angiogenesis; however, it remains unclear whether LLT can directly protect neurons against damage, and the underlying molecular mechanisms are poorly understood. Methods We investigated the neuroprotective effect of LLT against hydrogen peroxide (H2O2)-induced neuronal damage in cultured primary rat cortical neurons, as well as the potential underlying mechanisms. Neuronal viability and cell death assays were used to determine the effects of LLT on neuroprotection, while the mode of cell death was confirmed using flow cytometry. Changes in the expression of inflammatory factors involved in activation of the NLRP3 inflammasome were measured using immunocytochemistry (ICC) and confirmed by real-time PCR. And, we analyzed that the effect of LLT on neurotrophic factors secretion and synaptic connectivity using ICC in H2O2-induced neuron at 7 days in vitro. Results LLT effectively protected cultured rat cortical neurons from H2O2-induced injury by significantly inhibiting NLRP3 inflammasome activation. In addition, LLT significantly reduced caspase1 activation, which is known to be induced by inflammasome formation, and consequently regulated the secretion of IL-1β/IL-18. We demonstrated that LLT enhances axonal elongation and synaptic connectivity against H2O2-induced injury of rat primary cortical neuron. Conclusions Together, these results demonstrate that LLT can directly protect cultured cortical neurons from H2O2-induced neuronal damage by inhibiting NLRP3 inflammasome activation and the secretion of caspase-1 and IL-1β/IL-18. Thus, our study provides new insights into the therapeutic mechanisms of LLT and suggests that the NLRP3 inflammasome could be a promising target for treating neurological diseases.

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