BACKGROUND: High mobility group box-1 (HMGB1) is an endogenous danger signal that mediates activation of the innate immune response including NLR pyrin domain containing 3 (NLRP3) inflammasome activation and proinflammatory cytokine release. Although HMGB1 and NLRP3 have been implicated in the pathophysiology of seizures, the correlation between HMGB1 and NLRP3 expression has not been determined in children with febrile seizures (FS). To explore the relationship between extra-cellular HMGB1 and NLRP3 in children with FS, we analyzed serum HMGB1, NLRP3, caspase-1, and proinflammatory cytokines in patients with FS.
METHODS: Thirty children with FS and thirty age-matched febrile controls were included in this study. Blood was obtained from the children with FS within 1 h of the time of the seizure; subsequently, the serum contents of HMGB1, NLRP3, caspase-1, interleukin (IL)-1β, interleukin (IL)-6, and tumour necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. The Mann‒Whitney U test was used to compare serum cytokine levels between FS patients and controls. Spearman\'s rank correlation coefficient was calculated to detect significant correlations between cytokine levels.
RESULTS: Serum levels of HMGB1, NLRP3, caspase-1, IL-1β, IL-6, and TNF-α were significantly higher in FS patients than in febrile controls (p < 0.05). Serum levels of HMGB1 were significantly correlated with levels of NLRP3 and caspase-1 (both, p < 0.05). Serum levels of caspase-1 were significantly correlated with levels of IL-1β (p < 0.05). Serum levels of IL-1β were significantly correlated with levels of IL-6 and TNF-α (p < 0.05).
CONCLUSIONS: HMGB1 is up-regulated in the peripheral serum of FS patients, which may be responsible, at least in part, for the increased expression of NLRP3 and Caspase-1. Increased expression of caspase-1 was significantly associated with elevated serum levels of IL-1β. Given that activated Caspase-1 directly regulates the expression of mature IL-1β and positively correlates with activation of the NLRP3 inflammasome, our data suggest that increased levels of peripheral HMGB1 possibly mediate IL-1β secretion through the activation of the NLRP3 inflammasome in children with FS. Thus, both HMGB1 and NLRP3 might be potential targets for preventing or limiting FS.

UNASSIGNED: This study aimed to evaluate the gene expression of the P2X purinoceptor 7 (P2X7R)- nod-like receptor pyrin domain-containing protein 3 (NLRP3) signal pathway in peripheral blood mononuclear cells (PBMCs) between schizophrenia (SCZ) patients and healthy controls (HC) to reveal its relationship with clinical variables.
UNASSIGNED: Thirty-two SCZ patients and 41 healthy controls were included in this study. The Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS), The Global Assessment of Functioning (GAF) scale and the Functioning Assessment Short Test (FAST) scales were applied. P2X7R, NLRP3, IL-1β and IL-18 gene expression levels were evaluated by real-time polymerase chain reaction in PBMCs.
UNASSIGNED: NLRP3, P2RX7, IL-1β and IL-18 expression levels were significantly higher in PBMCs of SCZ patients than in HC subjects. Negative correlations were found between NLRP3 gene expression levels and GAF and FAST scales scores. There was a negative correlation between IL-18 expression levels and the GAF and FAST scales scores and a positive correlation with the SAPS scale scores.
UNASSIGNED: Systemic inflammation is implicated in SCZ pathogenesis, according to our findings, which suggest that the NLRP3 pathway may be involved. The NLRP3 inflammasome may serve as a biomarker for SCZ, and its pharmacological regulation may be a promising treatment approach.Key pointsWe hypothesised that the NLRP3 pathway may contribute to the etiopathogenesis of schizophrenia.NLRP3, IL-1β and IL-18 mRNA levels were higher in patients with schizophrenia compared to healthy controls.Negative correlations were found between NLRP3 gene expression levels and GAF and FAST scales scores.There was a negative correlation between IL-18 expression levels and the GAF and FAST scales scores.The SAPS scale scores and IL-18 expression levels had a positive correlation.Given all these findings, it can be stated that NLRP3 inflammasome may play a role in the pathogenesis and symptoms of schizophrenia.

The exact immunological mechanisms of post infectious bronchiolitis obliterans (PIBO) in childhood are not fully known. It has been shown that the inflammasome and IL-18 pathway play important roles in the pathogenesis of lung fibrosis. We aimed to investigate the role of caspase-1, IL-18, and IL-18 components in PIBO. From January to May 2020, children with PIBO, children with history of influenza infection without PIBO, and healthy children were asked to participate in the study in three pediatric pulmonology centers. Serum caspase-1, IL-18, IL-18BP, IL-18R, and INF-γ levels were measured by ELISA and compared between the 3 groups. There were 21 children in the PIBO group, 16 children in the influenza group, and 39 children in the healthy control group. No differences in terms of age and gender between the 3 groups were found. IL-18 and IL-18BP levels were higher in the healthy control group (p = 0.018, p = 0.005, respectively). IL-18R was higher in the PIBO group (p = 0.001) and caspase-1 was higher in the PIBO and influenza group than the healthy control group (p = 0.002). IFN-γ levels did not differ between the 3 groups. IL-18BP/IL-18 was higher in the influenza group than the PIBO group and the healthy control group (p = 0.003).
CONCLUSIONS: Caspase-1 level was increased in patients with PIBO which suggests that inflammasome activation may have a role in fibrosis; however, IL-18 level was found to be low. Mediators other than IL-18 may be involved in the inflammatory pathway in PIBO. Further immunological studies investigating inflammasome pathway are needed for PIBO with chronic inflammation.
BACKGROUND: • Post infectious bronchiolitis obliterans (PIBO) is a rare, severe chronic lung disease during childhood which is associated with inflammation and fibrosis which lead to partial or complete luminal obstruction especially in small airways. • The exact immunological mechanisms of PIBO in childhood are not fully known.
BACKGROUND: • Inflammasome activation persists even years after acute infection and may play a role in fibrosis in PIBO. • Mediators other than IL-18 may be involved in these inflammatory pathway.

Despite the recent attention focused on the roles of the NLRP3 inflammasome in the pathogenesis of metabolic and inflammatory diseases, little is known about the activation status of NLRP3 inflammasome in patients with nonalcoholic fatty liver disease (NAFLD). The present study aimed to investigate whether inflammasomes activation is upregulated in patients with NAFLD and the upregulation can be attenuated by anthocyanins, which are polyphenols with known anti-inflammatory activities.
This study included a case-control study and a randomized controlled intervention trial. In the first part, NAFLD patients and healthy controls were recruited from a cohort of railroad workers. In the second part, NAFLD patients were randomly assigned to receive either capsules of anthocyanins (320 mg daily) or placebo for 12 weeks. A series of genes and factors associated with activation of NLRP3 inflammasome in subjects\' plasma and peripheral blood mononuclear cells (PBMCs) were analyzed.
Compared with healthy controls, the mRNA levels of NLRP3 inflammasome components (NLRP3, caspase-1, interleukin (IL)-1β, and IL-18) were significantly upregulated in the PBMCs of NAFLD patients. Consistently, plasma levels of mature IL-1β and IL-18 in NAFLD patients were significantly higher than in controls. After anthocyanin administration, both mRNA expression of NLRP3 inflammasome components (caspase-1, IL-1β, and IL-18) in PBMCs and plasma levels of IL-1β and IL-18 decreased dramatically in NAFLD patients compared with controls.
This study has demonstrated that the activation of NLRP3 inflammasome is highly increased in NAFLD patients, but it can be markedly suppressed by anthocyanins, which provides a rationale for the development of anti-inflammatory therapies in NAFLD.

暂无摘要。

Several human diseases are thought to evolve due to a combination of host genetic mutations and environmental factors that include alterations in intestinal microbiota composition termed dysbiosis. Although in some cases, host genetics may shape the gut microbiota and enable it to provoke disease, experimentally disentangling cause and consequence in such host-microbe interactions requires strict control over non-genetic confounding factors. Mouse genetic studies previously proposed Nlrp6/ASC inflammasomes as innate immunity regulators of the intestinal ecosystem. In contrast, using littermate-controlled experimental setups, we recently showed that Nlrp6/ASC inflammasomes do not alter the gut microbiota composition. Our analyses indicated that maternal inheritance and long-term separate housing are non-genetic confounders that preclude the use of non-littermate mice when analyzing host genetic effects on intestinal ecology. Here, we summarize and discuss our gut microbiota analyses in inflammasome-deficient mice for illustrating the importance of littermate experimental design in studying host-microbiota interactions.

OBJECTIVE: Rituximab is a chimeric anti-CD20 IgG1 monoclonal antibody for the treatment of various forms of lymphoma and haematological autoimmune diseases. Interstitial lung disease is a rare but lethal pulmonary toxicity of rituximab. Nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a molecular platform activated upon signs of cellular \'danger\' to trigger the maturation of pro-inflammatory cytokines. We report the first case of rituximab-induced interstitial lung disease (R-ILD) with NLRP3 inflammasome activation in the lung.
METHODS: A 30-year-old male patient diagnosed with idiopathic thrombocytopenic purpura (ITP) was treated with four cycles of rituximab in one month. Three weeks after last rituximab administration, he developed progressive dyspnoea associated with respiratory failure, which was diagnosed as R-ILD. The patient showed a good response to steroid treatment, and lung biopsy was performed 5 days after the treatment. Immunohistopathological studies of lung specimens showed high expressions of inflammasome components NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1 in lung interstitium with a heavy infiltration of CD19-positive cells. The levels of inflammasome-related cytokines IL-1β and IL-18 in the serum were declined during the therapy.
CONCLUSIONS: This is the first report confirmed the role of NLRP3 inflammasome in pulmonary toxicity of rituximab. Inhibited activation of NLRP3 inflammasome in lung by steroid treatment could reverse R-ILD and block subsequent lung fibrosis. This result could open a new sight into the pathogenesis and provide a new target for the treatment of R-ILD.

Chronic, non-acute inflammation is behind conditions that represent most of the disease burden in humans and is clearly linked to immune and metabolic mechanisms. The convergence of pathways involving the immune response, oxidative stress, increased circulating lipids and aberrant insulin signaling results in CCL2-associated macrophage recruitment and altered energy metabolism. The CCL2/CCR2 pathway and the energy sensor AMP-activated protein kinase (AMPK) are attractive therapeutic targets as a part of preventive management of disease. Several effects of polyphenols are useful in this scenario, including a reduction in the activities of cytokines and modulation of cellular metabolism through histone deacetylase inhibitors, AMPK activators, calorie-restriction mimetics or epigenetic regulators. Research is currently underway to develop orally active drugs with these effects, but it is convenient to examine more closely what we are eating. If a lack of relevance in terms of toxicity and substantial effectiveness are confirmed, plant-derived components may provide useful druggable components and dietary supplements. We consider therapeutic actions as a combination of synergistic and/or antagonistic interactions in a multi-target strategy. Hence, improvement in food through enrichment with polyphenols with demonstrated activity may represent a major advance in the design of diets with both industrial and sanitary value.