Chun-Lei Jiang

NLRP3 Inflammasome Mediates Chronic Mild Stress-induced Depression in Mice via Neuroinflammation

Background: Evidence from both clinical and experimental research indicates that the immune-brain interaction plays a pivotal role in the pathophysiology of depression. A multi-protein complex of the innate immune system, the NLRP3 inflammasome regulates cleavage and secretion of proinflammatory cytokine interleukin-1β. The inflammasome detects various pathogen-associated molecule patterns and damage-associated molecule patterns, which then leads to a series of immune-inflammatory reactions. Methods: To explore the role of inflammasome activation in the underlying biological mechanisms of depression, we established a mouse model of depression with unpredictable chronic mild stress. Results: Mice subjected to chronic mild stress for 4 weeks had significantly higher serum corticosterone levels, serum interleukin-1β levels, and hippocampal active interleukin-1β protein levels. They also displayed depressive-like symptoms, including decreased sucrose preference and increased immobility time. Moreover, the hippocampi of chronic mild stress-exposed mice had significantly higher activity of caspase-1, which accompanied by higher protein levels of NLRP3 and the apoptotic speck-containing protein with a card. Pretreatment with the NLRP3 inflammasome inhibitor VX-765 decreased serum and hippocampal levels of interleukin-1β protein and significantly moderated the depressive-like behaviors induced by chronic mild stress. Conclusions: These data suggest the NLRP3 inflammasome mediates stress-induced depression via immune activation. Future procedures targeting the NLRP3 inflammasome may have promising effects in the prevention and treatment of depression.

Involvement of Inflammasome Activation in Lipopolysaccharide-induced Mice Depressive-like Behaviors

The NLRP3 inflammasome is a cytoplasmic multiprotein complex of the innate immune system that regulates the cleavage of interleukin‐1β and interleukin‐18 precursors. It can detect a wide range of danger signals and trigger a series of immune‐inflammatory reactions. There were plenty of studies indicating that activation of the immune system played pivotal roles in depression. However, the underlying mechanisms of immune‐depression interactions remained elusive and there was no report about the involvement of inflammasome activation in depression.

TNFα mediates stress-induced depression by upregulating indoleamine 2,3-dioxygenase in a mouse model of unpredictable chronic mild stress

Depression is often preceded by exposure to stressful life events. Chronic stress causes perturbations in the immune system, and up-regulates production of proinflammatory cytokines, which has been proposed to be associated with the pathogenesis of clinical depression. However, the potential mechanisms by which stress-induced proinflammatory cytokines lead to the development of depression are not well understood. Here, we sought to screen the main proinflammatory cytokines and the potential mechanisms linking inflammation to depression-like behavior during unpredictable, chronic, mild stress (UCMS), in vivo. Mice were allocated into four groups in each separate experiment: saline-control, saline-UCMS, drug-control and drug-UCMS. Development of depression-like behavior was reflected as a reduction in sucrose preference, and increased immobility in both the forced swim and tail suspension tests. The following drugs were administered intraperitoneally: the pan-anti-inflammatory tetracycline derivative, minocycline (30 mg/kg, daily), the tumor necrosis factor (TNF)α monoclonal antibody, infliximab (10 mg/kg, twice weekly), and the indoleamine 2, 3-dioxygenase (IDO) inhibitor, 1-methyltryptophan (1-MT, 10 mg/mouse, daily). Plasma TNFα, IL-1β and IL-18 increased significantly after the four-week UCMS exposure. Pretreatment of mice with minocycline completely blocked any upregulation. Concurrent with development of depression-like behaviors, the concentration of TNFα in plasma and the cerebral cortex increased remarkably. The tryptophan-degrading enzyme IDO was up-regulated in the cortex following UCMS exposure. Treatment of mice with minocycline, infliximab or 1-MT prevented the development of depression-like behaviors. Furthermore, blockade of TNFα inhibited expression of IDO and protected cortical neurons from UCMS-induced damage. These results suggest that TNFα plays a critical role in mediating UCMS-induced depression through up-regulation of IDO and subsequent damage of cortical neurons.

Mindfulness meditation for insomnia: A meta-analysis of randomized controlled trials

BACKGROUND Insomnia is a widespread and debilitating condition that affects sleep quality and daily productivity. Although mindfulness meditation (MM) has been suggested as a potentially effective supplement to medical treatment for insomnia, no comprehensively quantitative research has been conducted in this field. Therefore, we performed a meta-analysis on the findings of related randomized controlled trials (RCTs) to evaluate the effects of MM on insomnia. METHODS Related publications in PubMed, EMBASE, the Cochrane Library and PsycINFO were searched up to July 2015. To calculate the standardized mean differences (SMDs) and 95% confidence intervals (CIs), we used a fixed effect model when heterogeneity was negligible and a random effect model when heterogeneity was significant. RESULTS A total of 330 participants in 6 RCTs that met the selection criteria were included in this meta-analysis. Analysis of overall effect revealed that MM significantly improved total wake time and sleep quality, but had no significant effects on sleep onset latency, total sleep time, wake after sleep onset, sleep efficiency, total wake time, ISI, PSQI and DBAS. Subgroup analyses showed that although there were no significant differences between MM and control groups in terms of total sleep time, significant effects were found in total wake time, sleep onset latency, sleep quality, sleep efficiency, and PSQI global score (absolute value of SMD range: 0.44-1.09, all p<0.05). CONCLUSIONS The results suggest that MM may mildly improve some sleep parameters in patients with insomnia. MM can serve as an auxiliary treatment to medication for sleep complaints.

Ds-HMGB1 and Fr-HMGB Induce Depressive Behavior through Neuroinflammation in Contrast to Nonoxid-HMGB1.

High mobility group box 1 (HMGB1) has been implicated as a key factor in several neuroinflammatory conditions. Our previous study suggested that the release of central HMGB1 acts as a late-phase mediator in lipopolysaccharide (LPS)-induced depression. Recent findings indicate that the redox state of HMGB1 is a critical determinant of its immunomodulatory properties. Here, we aimed to investigate the potential mechanisms that link the redox states of HMGB1 to depression in mice. Distinct redox forms of recombinant HMGB1 (rHMGB1) were used that included fully reduced HMGB (fr-HMGB1), which acted as a chemokine, and disulfide-HMGB1 (ds-HMGB1), which possessed cytokine activity. Fr-HMGB1 in vivo was partially oxidized into ds-HMGB1; thus, the mutant protein non-oxidizable chemokine-HMGB (nonoxid-HMGB1) was applied. Concurrent with depressive behavior induced by four-week stress exposure, the HMGB1 concentrations in the serum and cerebral cortex substantially increased. Therefore, a single dose of rHMGB1 (200ng/5μl/mice) or vehicle was administered to mice via intracerebroventricular (i.c.v.) injection. The receptor inhibitors of TLR4/RAGE/CXCR4 (TAK-242/FPS-ZM1/AMD3100) (3mg/kg) were intraperitoneally injected 30min prior to rHMGB1 treatment. Depressive-like behavior was measured 20h post i.c.v. injection. Administration of fr-HMGB1 prolonged the immobility duration in the tail suspension test (TST) and decreased sucrose preference. In addition to depressive behavior, the hippocampal TNF-α protein slightly increased. These depressive behaviors and upregulation of hippocampal TNF-α were alleviated or abrogated by pretreatment with the inhibitors AMD3100, FPS-ZM1, and TAK-242. Alternatively, nonoxid-HMGB1 failed to induce TNF-α protein or prolong the immobility duration. As expected, ds-HMGB1 administration substantially upregulated hippocampal TNF-α protein, increased the immobility time in the TST and decreased sucrose preference. Moreover, both glycyrrhizin and TAK-242 improved ds-HMGB1-induced depressive behavior. Furthermore, TAK-242 significantly blocked the upregulation of hippocampal TNF-α protein and protected hippocampal myelin basic protein from ds-HMGB1-induced reduction. These drugs had no effect on the total or central distance in the open field test. Collectively, this initial experiment demonstrates the role and receptor mechanisms of HMGB1 under different redox states on the induction of depressive-like behavior. Both ds-HMGB1 and fr-HMGB1 may induce depressive-like behavior in vivo mainly via neuroinflammatory response activation.

High-mobility group box-1 was released actively and involved in LPS induced depressive-like behavior.

Depression disorder is a common mental illness, of which the pathogenesis is not well understood. Studies suggest that immunity imbalance and up-regulation of pro-inflammatory cytokines may be associated with the pathogenesis of depression. High-mobility group box 1 protein (HMGB1) has gained much attention as an important player in innate immune responses and an modulating factor in several inflammatory diseases. Here we sought to explore the role of HMGB1 in the development of depression. Depression model was established with low dose of lipopolysaccharide (LPS) administration. Depressive behavior was reflected with increased immobility time in tail suspension test. Accompanying with depressive-like behavior, translocation of HMGB1 from nuclei to cytoplasm was observed by immunofluorescence assays. Meanwhile, no significant necrosis was observed evaluated by hematoxylin-eosin staining. These data indicated that HMGB1 was released actively in the central nervous system. In addition, treating the mice with human recombinant HMGB1 (rHMGB1) could induce the development of depressive-like behavior. Blockage of HMGB1 with GZA abrogated the depressive-like behavior induced by LPS or rHMGB1. These results implicated that HMGB1 was involved in LPS-induced depressive-like behavior.

High-salt diet enhances hippocampal oxidative stress and cognitive impairment in mice

Previous evidence suggests that a high-salt (HS) diet may increase oxidative stress and contribute to the development of hypertension that is already present. Oxidative stress is thought to play a critical role in the development of neurodegenerative diseases. Lower dietary sodium intake putatively contributes to a lower rate of cognitive impairment; however, the specific effects of HS diet on cognitive function remain poorly understood. In this work, C57BL/6J mice were administered a normal-salt (NS) diet (0.4% NaCl) or a HS diet (7.0% NaCl) for 12 weeks, and cognitive ability and oxidative stress in the brain were measured. It was found that the HS diet significantly impaired retention of spatial memory. Additionally, superoxide anion production in the hippocampus was significantly increased in the HS diet mice compared with that in the NS mice. Interestingly, the antioxidant defense capacities for HS diet mice were markedly reduced in the hippocampus, but not in the cerebral cortex, compared with the NS mice. Taken together, these data demonstrate that HS diet directly impairs retention of spatial memory, which may be related to the increased oxidative stress observed in the hippocampus.

Inflammation: The Common Pathway of Stress-Related Diseases

While modernization has dramatically increased lifespan, it has also witnessed that the nature of stress has changed dramatically. Chronic stress result failures of homeostasis thus lead to various diseases such as atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and depression. However, while 75%–90% of human diseases is related to the activation of stress system, the common pathways between stress exposure and pathophysiological processes underlying disease is still debatable. Chronic inflammation is an essential component of chronic diseases. Additionally, accumulating evidence suggested that excessive inflammation plays critical roles in the pathophysiology of the stress-related diseases, yet the basis for this connection is not fully understood. Here we discuss the role of inflammation in stress-induced diseases and suggest a common pathway for stress-related diseases that is based on chronic mild inflammation. This framework highlights the fundamental impact of inflammation mechanisms and provides a new perspective on the prevention and treatment of stress-related diseases.

NLRP3 gene knockout blocks NF-κB and MAPK signaling pathway in CUMS-induced depression mouse model.

Background Abundant researches indicate that neuroinflammation has important roles in the pathophysiology of depression. Our previous study found that the NLRP3 inflammasome mediated stress‐induced depression‐like behavior in mice via regulating neuroinflammation. However, it still remains unclear that how the NLRP3 inflammasome influences related inflammatory signaling pathway to contribute to neuroinflammation in depression. Methods We used wild‐type mice and NLRP3 gene knockout mice to explore the role of NLRP3 inflammasome and related inflammatory signaling pathways in chronic unpredictable mild stress (CUMS) induced depression mouse model. Results Both wild‐type and NLRP3 knockout stress group mice gained less weight than control group mice after 4 weeks CUMS exposure. The wild‐type mice subjected to 4 weeks CUMS displayed depression‐like behaviors, including decreased sucrose preference and increased immobility time in the tail suspension test. The NLRP3 knockout stress group mice didn’t demonstrate depression‐like behaviors. The levels of interleukin‐1&bgr; protein in serum and hippocampi of CUMS exposed wild‐type mice were significantly higher, while the NLRP3 knockout stress group mice didn’t show an elevation of interleukin‐1&bgr; levels. Similarly to early researches, we found that CUMS led to promoted NLRP3 expression in hippocampi. In addition, the hippocampi in CUMS exposed wild‐type mice had higher p‐JNK and p‐p38 protein expression, which indicated activation of the mitogen‐activated protein kinases (MAPK) pathway. The knockout of NLRP3 gene inhibited CUMS‐induced activation of the MAPK pathway. The nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐&kgr;B) protein complex was activated in the hippocampi of wild‐type mice after CUMS exposure, while knockout of NLRP3 gene hindered its activation. Conclusions These data further proved that the NLRP3 inflammasome mediated CUMS‐induced depression‐like behavior. The NLRP3 inflammasome regulated CUMS‐induced MAPK pathway and NF‐&kgr;B protein complex activation in depression mouse model. Further researches targeting the NLRP3 inflammasome‐signaling pathway might be under a promising future in the prevention and treatment of depression. HighlightsCUMS‐induced depression‐like behavior needs participation of NLRP3 inflammasome.NLRP3 gene knockout blocks activation of NF‐&kgr;B protein complex in CUMS‐induced depression mouse model.The NLRP3 inflammasome regulates CUMS‐induced MAPK pathway activation.

Effects of hydrogen-rich water on depressive-like behavior in mice

Emerging evidence suggests that neuroinflammation and oxidative stress may be major contributors to major depressive disorder (MDD). Patients or animal models of depression show significant increase of proinflammatory cytokine interleukin-1β (IL-1β) and oxidative stress biomarkers in the periphery or central nervous system (CNS). Recent studies show that hydrogen selectively reduces cytotoxic oxygen radicals, and hydrogen-rich saline potentially suppresses the production of several proinflammatory mediators. Since current depression medications are accompanied by a wide spectrum of side effects, novel preventative or therapeutic measures with fewer side effects might have a promising future. We investigated the effects of drinking hydrogen-rich water on the depressive-like behavior in mice and its underlying mechanisms. Our study show that hydrogen-rich water treatment prevents chronic unpredictable mild stress (CUMS) induced depressive-like behavior. CUMS induced elevation in IL-1β protein levels in the hippocampus, and the cortex was significantly attenuated after 4 weeks of feeding the mice hydrogen-rich water. Over-expression of caspase-1 (the IL-1β converting enzyme) and excessive reactive oxygen species (ROS) production in the hippocampus and prefrontal cortex (PFC) was successfully suppressed by hydrogen-rich water treatment. Our data suggest that the beneficial effects of hydrogen-rich water on depressive-like behavior may be mediated by suppression of the inflammasome activation resulting in attenuated protein IL-1β and ROS production.