Evidence from previous studies indicates that neuroinflammation contributes to the onset of Alzheimer’s Disease (AD). Moreover, cellular dysfunction is induced by impaired signaling of ...neurotransmitters. This study aimed to explore the correlation between cellular immune dysfunction and neurotransmitter changes through cranial Magnetic Resonance Spectroscopy (MRS) in AD patients.
Here, 32 AD, 40 Vascular Dementia (VD), and 35 Non-Dementia Elderly Control (NDE) cases were enrolled. Flow cytometry was performed to characterize lymphocyte subsets in plasma samples. The IL-1β and Caspase-1 levels were detected by ELISA. The NLRP3 expression level was measured by Western Blot (WB). The equivalence of N-acetylaspartate (NAA), Creatine (Cr), Choline (Cho), and Inositol (MI) in bilateral hippocampi of patients was examined by MRS. The association of NAA/Cr or MI/Cr ratios with the proportion of T lymphocyte subsets or NK cell subsets was determined through single-factor correlation analysis.
The proportion of T lymphocyte subsets was significantly lower in the AD group than in the NDE group (P < 0.01). On the other hand, the Caspase-1, NLRP3, and IL-1β protein expression levels were significantly higher in the AD group than in the other groups. Further analysis showed that the NAA/Cr ratio was lower in the AD group than in the NDE group. Additionally, a significant positive correlation was found between the NAA/Cr ratio and the MMSE score (r = 0.81, P < 0.01). Moreover, a significant positive correlation was observed between the NAA/Cr and T lymphocyte ratios. The NAA/Cr ratio was significantly negatively correlated with the proportion of NK cells in the blood (r = －0.83, P < 0.01). A significant negative correlation was also recorded between the MI/Cr and T cell ratios in blood samples.
Impaired cellular immune dysfunction in AD patients was significantly correlated with abnormal MRS. Neuroimmune dysfunction may contribute to the pathogenesis of AD and alter the metabolism of neurotransmitters such as aspartic acid and MI in the brains of AD patients.
Not applicable.
•Cognitive dysfunction in AD patients is positively correlated with the decline of cellular immune function.•Decreased T lymphocyte subsets were significantly associated with NLRP3 inflammasome activation.•Cognitive dysfunction in AD patients is positively correlated with the decrease of NAA/Cr in the brain.•Decreased cellular immune function in AD patients was significantly correlated with abnormal MRS.
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•The present review recapitulates relevant findings related to the role of the receptors of the innate immune system (TLRs and NLRs) in the progression of the most prevalent ...CVDs.•TLRs and NLRs play a key role in the progression of atherosclerosis, acute myocardial infarction or heart failure.•The development of new specific strategies to impair exacerbated TLR and NLR activation in CVDs are strong candidates for therapy and opens a new research field.
Cardiovascular diseases (CVDs) are the leading cause of death in the industrialized world. Most CVDs are associated with increased inflammation that arises mainly from innate immune system activation related to cardiac damage. Sustained activation of the innate immune system frequently results in maladaptive inflammatory responses that promote cardiovascular dysfunction and remodeling. Much research has focused on determining whether some mediators of the innate immune system are potential targets for CVD therapy. The innate immune system has specific receptors—termed pattern recognition receptors (PRRs)—that not only recognize pathogen-associated molecular patterns, but also sense danger-associated molecular signals. Activation of PRRs triggers the inflammatory response in different physiological systems, including the cardiovascular system. The classic PRRs, toll-like receptors (TLRs), and the more recently discovered nucleotide-binding oligomerization domain-like receptors (NLRs), have been recently proposed as key partners in the progression of several CVDs (e.g., atherosclerosis and heart failure). The present review discusses the key findings related to the involvement of TLRs and NLRs in the progression of several vascular and cardiac diseases, with a focus on whether some NLR subtypes (nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing receptor 3 and nucleotide-binding oligomerization domain-containing protein 1) can be candidates for the development of new therapeutic strategies for several CVDs.
Inflammation and pyroptosis have crucial impacts on the development of acute kidney injury (AKI) and have been validated in a variety of existing AKI animal models. However, the mechanisms underlying ...wasp venom-induced AKI are still unclear. The involvement of nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) in some mouse models of AKI has been extensively documented, and its crucial function in controlling inflammation and pyroptosis has been highlighted. The objective of our study was to investigate the role and mechanism of NLRP3 in inflammation and pyroptosis associated with wasp venom-induced AKI.
A mouse model of AKI induced by wasp venom pre-injected with an NLRP3 inhibitor was used to study the role and mechanism of NLRP3. To verify the importance of NLRP3, western blotting was performed to assess the expression of NLRP3, caspase-1 p20, and gasdermin D (GSDMD)-N. Additionally, quantitative real-time polymerase was used to determine the expression of NLRP3, caspase-1, and GSDMD. Furthermore, enzyme-linked immunosorbent assay was utilized to measure the levels of interleukin (IL)-1β and IL-18.
NLRP3 was found to be the downstream signal of the stimulator of interferon genes in the wasp sting venom-induced AKI model. The administration of wasp venom in mice significantly upregulated the expression of NLRP3, leading to renal dysfunction, inflammation, and pyroptosis. Treatment with an NLRP3 inhibitor reversed the renal damage induced by wasp venom and attenuated pathological injury, inflammatory response, and pyroptosis.
NLRP3 activation is associated with renal failure, inflammatory response and pyroptosis in the hyper early phase of wasp venom-induced AKI. The inhibition of NLRP3 significantly weakened this phenomenon. These findings could potentially offer a viable therapeutic approach for AKI triggered by wasp venom.
Background
Pattern recognition receptors (PRRs) orchestrate the innate immune defence in human biliary epithelial cells (BECs). Tight control of PRR signalling provides tolerance to physiological ...amounts of intestinal endotoxins in human bile to avoid constant innate immune activation in BECs.
Aims
We wanted to determine whether inappropriate innate immune responses to intestinal endotoxins contribute to the development and perpetuation of chronic biliary inflammation.
Methods
We examined PRR‐mediated innate immune responses and protective endotoxin tolerance in primary BECs isolated from patients with primary sclerosing cholangitis (PSC), alcoholic liver disease and patients without chronic liver disease. Expression studies comprised northern blots, RT‐PCR, Western blots and immunocytochemistry. Functional studies comprised immuno‐precipitation Western blots, FACS for endotoxin uptake, and NF‐κB activation assays and ELISA for secreted IL‐8 and tumour necrosis factor (TNF)‐α.
Results
Primary BECs from explanted PSC livers showed reversibly increased TLR and NOD protein expression and activation of the MyD88/IRAK signalling complex. Consecutively, PSC BECs exhibited inappropriate innate immune responses to endotoxins and did not develop immune tolerance after repeated endotoxin exposures. This endotoxin hyper‐responsiveness was probably because of the stimulatory effect of abundantly expressed IFN‐γ and TNF‐α in PSC livers, which stimulated TLR4‐mediated endotoxin signalling in BECs, leading to increased TLR4‐mediated endotoxin incorporation and impaired inactivation of the TLR4 signalling cascade. As TNF‐α inhibition partly restored protective innate immune tolerance, endogenous TNF‐α secretion probably contributed to inappropriate endotoxin responses in BECs.
Conclusion
Inappropriate innate immune responses to intestinal endotoxins and subsequent endotoxin intolerance because of enhanced PRR signalling in BECs probably contribute to chronic cholangitis.
Oxidized-low density lipoprotein (ox-LDL) can induce injury of endothelial cells, causing atherosclerosis, which is an important initial event in several cardiovascular diseases. Long non-coding RNAs ...(lncRNAs) have emerged as regulators of diverse biological processes, but their specific biological functions and biochemical mechanisms in ox-LDL-induced endothelial cell injury have not been well investigated. Here, we describe the initial functional analysis of a poorly characterized human lncRNA ZEB1 antisense 1 (ZEB1-AS1). We found that ox-LDL treatment could induce a decreased cell viability and an increased cell apoptosis in endothelial cells, and knockdown of ZEB1-AS1 significantly reversed this effect. Mechanistically, ox-LDL treatment could sequester p53 from binding to ZEB1-AS1 promoter region, causing transcriptional activation and upregulation of ZEB1-AS1. Moreover, enhanced ZEB1-AS1 could upregulate Nucleotide-Binding Oligomerization Domain 2 (NOD2) expression through recruiting leucine-rich pentatricopeptide repeat motif-containing protein (LRPPRC) to stabilize NOD2 mRNA. Experimental data showed that knockdown of NOD2 or LRPPRC dramatically abrogated the functional role of ZEB1-AS1 in ox-LDL-induced endothelial cell injury. In summary, we demonstrated that lncRNA ZEB1-AS1 regulates the ox-LDL-induced endothelial cell injury via an LRPPRC-dependent mRNA stabilization mechanism. Therefore, ZEB1-AS1 may serve as a multi-potency target to overcome endothelial cell injury, atherosclerosis and other cardiovascular diseases.
The study investigated the pathogenesis of Yao syndrome (YAOS), a rare systemic autoinflammatory disease associated with the nucleotide-binding oligomerization domain containing 2 (NOD2) gene ...variants.
RNA sequencing analyses were used to detect transcriptomic profile changes. Immunoblot and immunohistochemistry were used to examine the NOD2-mediated inflammatory signaling pathways and ELISA was used to detect cytokines.
Transcriptome analysis of YAOS revealed NOD-like receptor signaling pathway enrichment. Compared with HCs, P-RIP2, p-p65, p-p38, p-ERK, and p-JNK notably increased in PBMCs of a patient with YAOS. P-RIP2, p-p65, and p-p38 elevated in small intestinal mucosa tissues. P-p65 and p-p38 in synovial tissues from YAOS were higher than those in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Serum interleukin (IL)-6 level along with tumor necrosis factor (TNF)-α and IL-6 secreted from PBMCs were markedly higher in patients with YAOS in comparison to healthy controls (HCs). The supernatants of synovial cells from a patient with YAOS showed substantially higher IL-1β and IL-6 levels than those of RA and OA. Canakinumab therapy of a Q902K heterozygous patient with YAOS resulted in notable clinical improvement.
Overproduction of pro-inflammatory cytokines and the hyperactivation of NOD2-mediated signaling pathways were found in the NOD2 variant Q902K patient with YAOS. NOD2-RIP2-MAPK pathway might play a pivotal role in the pathogenesis of YAOS. These results provide new perspectives for targeted therapies in YAOS.
Inflammatory mediators are known to be elevated in association with decompression from elevated ambient pressure, but their role in tissue damage or overt decompression sickness is unclear. ...Circulating microparticles (MPs) are also known to increase, and because interleukin (IL)-1β is packaged within these particles, we hypothesized that IL-1β was responsible for tissue injuries. Here, we demonstrate that elevations of circulating MPs containing up to ninefold higher concentrations of IL-1β occur while mice are exposed to high air pressure (790 kPa), whereas smaller particles carrying proteins specific to exosomes are not elevated. MPs number and intra-particle IL-1β concentration increase further over 13 h post decompression. MPs also exhibit intra-particle elevations of tumor necrosis factor-α, caspase-1, inhibitor of κB kinase-β, and inhibitor of κB kinase-γ, and elevated IL-6 is adsorbed to the surface of MPs. Contrary to lymphocytes, neutrophil nucleotide-binding oligomerization domain-like receptor, pyrin domain containing 3 (NLRP3) inflammasome oligomerization and cell activation parameters occur during high pressure exposure, and additional evidence for activation is manifested post decompression. Diffuse vascular damage, although not apparent immediately post decompression, was present 2 h later and remained elevated for at least 13 h. Prophylactic administration of an IL-1β receptor inhibitor or neutralizing antibody to IL-1β inhibited MPs elevations, increases of all MPs-associated pro-inflammatory agents, and vascular damage. We conclude that an auto-activation process triggered by high pressure stimulates MPs production and concurrent inflammasome activation, and IL-1β is a proximal factor responsible for further cytokine production and decompression-associated vascular injuries.
Elevations in circulating microparticles due to decompression have been documented in humans and animals. This report shows that intra-particle interleukin-1β causes vascular damage that can be abrogated by interventions directed against this cytokine.
Changes in the expression of nucleotide-binding oligomerization domain containing 2 (NOD2) play an important role in the pathogenesis of several autoimmune diseases, such as inflammatory bowel ...diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). It seems that epigenetic modifications, including DNA methylation, have an important role in the suppression of gene activity. In this study, the relationship between DNA methylation patterns of the promoter region of the NOD2 gene and the pathogenesis of CD was assessed. Colonic mucosal samples were obtained from 15 Iranian patients with CD and 15 matched healthy controls with no history of autoimmune diseases. After bisulfite conversion of genomic DNA, the DNA methylation status of three CpG sites in the promoter region of the NOD2 gene was determined by the real-time quantitative multiplex methylation-specific PCR assay. Using this approach, we identified a decreased level of methylation of the NOD2 promoter in the colonic mucosa of patients with CD (0.128±0.093 vs. 0.025±0.016, unmethylated DNA in CD vs. healthy controls, respectively, P<0.000). According to our findings, promoter hypomethylation of the NOD2 gene in the colonic mucosa might contribute to the development and severity of CD.
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