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Roseburia intestinalis?derived flagellin ameliorates colitis by targeting miR?223?3p?mediated activation of NLRP3 inflammasome and pyroptosis.

ABSTRACT: Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD), which is a chronic, relapsing condition associated with the disorder of gut microbial communities. A previous study reported that levels of Roseburia intestinalis (R.I), a butyrate?producing bacterium, are significantly decreased in patients with IBD and exert an anti?inflammatory function in dextran sulfate sodium (DSS)?induced colitis. However, the role of R.I flagellin in UC and its underlying molecular mechanism are not yet fully understood. Therefore, a DSS?induced colitis model in C57Bl/6 mice and the LPS/ATP?induced THP?1 macrophages were treated with R.I flagellin, which were used to investigate the anti?inflammatory effects of R.I flagellin. The results demonstrated that R.I flagellin decreased colitis?associated disease activity index, colonic shortening and the pathological damage of the colon tissues in murine colitis models. Furthermore, R.I flagellin decreased the serum levels of proinflammatory cytokines and inhibited activation of the nucleotide?binding oligomerization segment?like receptor family 3 (NLRP3) inflammasome in murine colitis. R.I flagellin was also demonstrated to decrease the Gasdermin D to yield the N?terminal fragment membrane pore and inhibit inflammasome?triggered pyroptosis. In vitro analysis indicated that microRNA (miR)?223?3p was involved in the regulation of R.I flagellin on NLRP3 inflammasome activation. Taken together, the results of the present study demonstrated that R.I flagellin inhibited activation of the NLRP3 inflammasome and pyroptosis via miR?223?3p/NLRP3 signaling in macrophages, suggesting that R.I flagellin may be used as a novel probiotic product for the treatment of UC.

SUBMITTER: Wu X

PROVIDER: S-EPMC7453595 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Roseburia intestinalis‑derived flagellin ameliorates colitis by targeting miR‑223‑3p‑mediated activation of NLRP3 inflammasome and pyroptosis.

Wu Xing X Pan Shiyu S Luo Weiwei W Shen Zhaohua Z Meng Xiangrui X Xiao Mengwei M Tan Bei B Nie Kai K Tong Ting T Wang Xiaoyan X

Molecular medicine reports 20200723 4

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD), which is a chronic, relapsing condition associated with the disorder of gut microbial communities. A previous study reported that levels of Roseburia intestinalis (R.I), a butyrate‑producing bacterium, are significantly decreased in patients with IBD and exert an anti‑inflammatory function in dextran sulfate sodium (DSS)‑induced colitis. However, the role of R.I flagellin in UC and its underlying molecular mechanism are not y ...[more]

PMID: 32700754

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Project description:Chronic obstructive pulmonary disease (COPD) is characterized by irreversible and progressive airflow limitation and encompasses a spectrum of diseases, including chronic obstructive bronchitis and emphysema. Pyroptosis is a unique form of inflammatory cell death mediated by the activation of caspase‑1 and inflammasomes. The long non‑coding RNA (lncRNA) growth arrest‑specific 5 (GAS5) is a well‑documented tumor suppressor, which is associated with cell proliferation and death in various diseases. The aim of the present study was to evaluate whether lncRNA GAS5 is associated with the pyroptosis in COPD. To create a COPD cell model, MRC‑5 cells were treated with 10 µg/ml lipopolysaccharide (LPS) for 48 h. Then the level of pro‑caspase 1, caspase 1, IL‑1β, IL‑18, NLRP3 and cleaved gasdermin D (GSDMD) was examined by western blotting. GAS5 mRNA level was detected by qualitative PCR following LPS treatment in MRC‑5 cells. Subsequently, IL‑2, IL‑6, IL‑10 and TNF‑α in MRC‑5 cells was measured by ELISA. Then the proliferation ability of MRC‑5 cells was detected by CCK‑8. Cell death was detected by TUNEL assay. LDH release was measured using an LDH Cytotoxicity Assay kit. The Magna RIP kit was used to validate the interaction between GAS5 and miR‑223‑3p. The present study revealed that increased expression levels of caspase‑1, IL‑1β, IL‑18 and cleaved GSDMD were observed in LPS‑treated MRC‑5 cells, indicating that pyroptosis is involved in COPD progression. Additionally, LPS induced the increase in GAS5 mRNA expression levels and the release of inflammatory factors (IL‑2, IL‑6, IL‑10 and TNF‑α), suggesting that GAS5 is implicated in pyroptosis in COPD. Furthermore, upregulation of GAS5 promoted cell death and inhibited proliferation in the MRC‑5 cell line. Additionally, increased GAS5 expression significantly promoted the production of caspase‑1, IL‑1β, IL‑18, cleaved GSDMD and NLR pyrin domain containing protein 3 (NLRP3). A dual‑luciferase assay demonstrated that GAS5 could directly bind to microRNA‑223‑3p (miR‑223‑3p), and NLRP3 is a direct target of miR‑223‑3p. Furthermore, GAS5 reduced the expression levels of miR‑223‑3p, while it increased the expression levels of NLRP3. The present study concluded that lncRNA GAS5 promoted pyroptosis in COPD by targeting the miR‑223‑3p/NLRP3 axis, implying that GAS5 could be a potential target for COPD.

Project description:BackgroundMitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation.MethodsReactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.ResultsCellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.ConclusionTaken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.

Dataset Information

Roseburia intestinalis?derived flagellin ameliorates colitis by targeting miR?223?3p?mediated activation of NLRP3 inflammasome and pyroptosis.

Publications

Roseburia intestinalis‑derived flagellin ameliorates colitis by targeting miR‑223‑3p‑mediated activation of NLRP3 inflammasome and pyroptosis.

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