BackgroundNLRP3 inflammasome is involved in the inflammatory responses during acute lung injury (ALI). RIP3 triggered NLRP3 inflammasome activation independent of necroptosis induction has recently been documented. In this study, the role of RIP3 in the activation of NLRP3 inflammasome in the development of ALI was investigated.MethodsA selective RIP3 inhibitor GSK872 was used to investigate the roles of RIP3 in NLRP3 inflammasome activation in the lipopolysaccharide (LPS) induced ALI mouse model. The mechanism of NLRP3 inflammasome activation was investigated in the human monocytic cell line THP-1. NLRP3 inflammasome and necroptosis were measured by flow cytometry or western blot. RIP3–NLRP3 interaction was interrogated using immunoprecipitation and the Duolink® In situ detection.ResultsSignificant upregulation of both necroptosis and NLRP3 inflammasome pathways were observed in the lungs of mice with LPS induced ALI. GSK872 significantly suppressed the activation of necroptosis and NLRP3 activation with reduction of IL-1β and IL-18 production and inflammatory cells infiltration, resulting in a significant amelioration of lung injury. These two processes were shown to be active in interstitial macrophages and CD11b+ monocyte–macrophages/dendritic cells. In THP-1 cells, RIP3 and NLRP3 interaction was enhanced by LPS/ATP stimulation resulting in IL-1β and IL-18 production. This RIP3–NLRP3 interaction was significantly inhibited by GSK872.ConclusionTaking together, these results show that RIP3 participates in the NLRP3 inflammasome activation in infiltrating macrophages in ALI induced by LPS. This process plays a significant pathogenic role in LPS-induced lung injury.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1606-4) contains supplementary material, which is available to authorized users.

Background The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a significant number of mortalities worldwide. COVID-19 poses a serious threat to human life. The clinical manifestations of COVID-19 are diverse and severe and 20% of infected patients are reported to be in a critical condition. A loss in lung function and pulmonary fibrosis are the main manifestations of patients with the severe form of the disease. The lung function is affected, even after recovery, thereby greatly affecting the psychology and well-being of patients, and significantly reducing their quality of life. Methods Participants must meet the following simultaneous inclusion criteria: over 18 years of age, should have recovered from severe or critical COVID-19 cases, should exhibit pulmonary fibrosis after recovery, and should exhibit Qi-Yin deficiency syndrome as indicated in the system of traditional Chinese medicine (TCM). The eligible candidates will be randomized into treatment or control groups. The treatment group will receive modern medicine (pirfenidone) plus TCM whereas the control group will be administered modern medicine plus TCM placebo. The lung function index will be continuously surveyed and recorded. By comparing the treatment effect between the two groups, the study intend to explore whether TCM can improve the effectiveness of modern medicine in patients with pulmonary fibrosis arising as a sequelae after SARS-CoV-2 infection. Discussion Pulmonary fibrosis is one of fatal sequelae for some severe or critical COVID-19 cases, some studies reveal that pirfenidone lead to a delay in the decline of forced expiratory vital capacity, thereby reducing the mortality partly. Additionally, although TCM has been proven to be efficacious in treating pulmonary fibrosis, its role in treating pulmonary fibrosis related COVID-19 has not been explored. Hence, a multicenter, parallel-group, randomized controlled, interventional, prospective clinical trial has been designed and will be conducted to determine if a new comprehensive treatment for pulmonary fibrosis related to COVID-19 is feasible and if it can improve the quality of life of patients. Trial registration: This multicenter, parallel-group, randomized controlled, interventional, prospective trial was registered at the Chinese Clinical Trial Registry (ChiCTR2000033284) on 26th May 2020 (prospective registered).

NLRP3 inflammasome has emerged as a crucial regulator of inflammatory bowel disease (IBD) characterized by a chronic inflammatory disease of the gastrointestinal tract. The expression of MCT4 is significantly increased in intestinal mucosal tissue of IBD, which has been identified to regulate intestinal barrier function. However, the function of MCT4 in cell pyroptosis remained unknown. In this study, we have established a stable cell line with MCT4 overexpression in HT-29 and CaCO2 cells, respectively. Functional analysis revealed that ectopic expression of MCT4 in CaCO2 cells contributed to cell pyroptosis as evidenced by LDH assay, which is largely attributed to Caspase-1-mediated canonical pyroptosis, but not Caspase-4 and Caspase-5, leading to cleave pro-IL-1β and IL-18 into mature form and release mediated by cleaved GSDMD. Mechanically, MCT4 overexpression in HT-29 and CaCO2 cell triggered the phosphorylation of ERK1/2 and NF-κB p65, while inhibition of MCT4 by MCT inhibitor α-Cyano-4-hydroxycinnamic acid (α-CHCA) in HT-29 and CaCO2 cells led to a significant downregulation of ERK1/2 and NF-κB activity. What’s more, blockade of ERK1/2-NF-κB pathway could reverse the promotion effect of MCT4 on IL-1β expression. Importantly, both MCT4 and Caspase-1, GSDMD were significantly increased in patients with IBD, and a positive clinical correlation between MCT4 and Caspase-1 expression was observed (p < 0.001). Taken together, these findings suggested that MCT4 promoted Caspase-1-mediated canonical cell pyroptosis to aggravate intestinal inflammation in intestinal epithelial cells (IECs) through the ERK1/2-NF-κB pathway.

Background More people ascend to high altitude (HA) for various activities, and some individuals are susceptible to HA illness after rapidly ascending from plains. Acute mountain sickness (AMS) is a general complaint that affects activities of daily living at HA. Although genomic association analyses suggest that single nucleotide polymorphisms (SNPs) are involved in the genesis of AMS, no major gene variants associated with AMS-related symptoms have been identified. Methods In this cross-sectional study, 604 young, healthy Chinese Han men were recruited in June and July of 2012 in Chengdu, and rapidly taken to above 3700 m by plane. Basic demographic parameters were collected at sea level, and heart rate, pulse oxygen saturation (SpO 2 ), systolic and diastolic blood pressure and AMS-related symptoms were determined within 18–24 h after arriving in Lhasa. AMS patients were identified according to the latest Lake Louise scoring system (LLSS). Potential associations between variant genotypes and AMS/AMS-related symptoms were identified by logistic regression after adjusting for potential confounders (age, body mass index and smoking status). Results In total, 320 subjects (53.0%) were diagnosed with AMS, with no cases of high-altitude pulmonary edema or high-altitude cerebral edema. SpO 2 was significantly lower in the AMS group than that in the non-AMS group ( P = 0.003). Four SNPs in hypoxia-inducible factor-related genes were found to be associated with AMS before multiple hypothesis testing correction. The rs6756667 ( EPAS1 ) was associated with mild gastrointestinal symptoms ( P = 0.013), while rs3025039 ( VEGFA ) was related to mild headache ( P = 0.0007). The combination of rs6756667 GG and rs3025039 CT/TT further increased the risk of developing AMS ( OR = 2.70, P < 0.001). Conclusions Under the latest LLSS, we find that EPAS1 and VEGFA gene variants are related to AMS susceptibility through different AMS-related symptoms in the Chinese Han population; this tool might be useful for screening susceptible populations and predicting clinical symptoms leading to AMS before an individual reaches HA. Trial registration Chinese Clinical Trial Registration, ChiCTR-RCS-12002232 . Registered 31 May 2012.