Immunopharmacology and immunotoxicology · 2023
miR-155-5p/FOXO3a promotes pulmonary fibrosis in rats by mediating NLRP3 inflammasome activation.
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Wu Ling, Pu Li, Zhuang Zhifang
Аннотация
OBJECTIVE: Pulmonary fibrosis (PF) is regarded as progressive lung disease. miR-155-5p depletion exerts anti-fibrotic effects in silicotic mice. This study explored the effect and possible mechanism of miR-155-5p in PF rats, hoping to find a new target for PF management.
METHODS: Bleomycin-induced PF rat model was established. Alveolar structure and collagen fiber deposition were observed by HE and Elastica-Masson staining. Alveolitis and PF scores were evaluated using the method of Szapiel. Total collagen content was detected using the Sircol method. PF rats were intraperitoneally injected with NLRP3 inhibitor MCC950 or intravenously injected with miR-155-5p antagomir and si-FOXO3a lentivirus plasmids. Binding sites of miR-155-5p and FOXO3a were predicted using bioinformatics analysis and dual-luciferase reporter assay. The expressions of miR-155-5p, NLRP3, ASC, caspase-1, IL-1β, IL-18, and FOXO3a were detected by RT-qPCR, Western blot, and ELISA.
RESULTS: MCC950 treatment inhibited NLRP3 inflammasome, alleviated alveolar hemorrhage and alveolitis, and reduced blue collagen fiber deposition, scores of alveolitis and PF, and levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 in PF rats. miR-155-5p was elevated in lung tissues of PF rats. Inhibition of miR-155-5p downregulated levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 in lung tissues of PF rats. miR-155-5p targeted FOXO3a. miR-155-5p inhibition and silencing FOXO3a exacerbated alveolitis and PF in rats and increased levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18.
CONCLUSIONS: miR-155-5p aggravated alveolitis and promoted PF by targeting FOXO3a and prompting the activation of NLRP3 inflammasome and then inducing IL-1β and IL-18 release.
METHODS: Bleomycin-induced PF rat model was established. Alveolar structure and collagen fiber deposition were observed by HE and Elastica-Masson staining. Alveolitis and PF scores were evaluated using the method of Szapiel. Total collagen content was detected using the Sircol method. PF rats were intraperitoneally injected with NLRP3 inhibitor MCC950 or intravenously injected with miR-155-5p antagomir and si-FOXO3a lentivirus plasmids. Binding sites of miR-155-5p and FOXO3a were predicted using bioinformatics analysis and dual-luciferase reporter assay. The expressions of miR-155-5p, NLRP3, ASC, caspase-1, IL-1β, IL-18, and FOXO3a were detected by RT-qPCR, Western blot, and ELISA.
RESULTS: MCC950 treatment inhibited NLRP3 inflammasome, alleviated alveolar hemorrhage and alveolitis, and reduced blue collagen fiber deposition, scores of alveolitis and PF, and levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 in PF rats. miR-155-5p was elevated in lung tissues of PF rats. Inhibition of miR-155-5p downregulated levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 in lung tissues of PF rats. miR-155-5p targeted FOXO3a. miR-155-5p inhibition and silencing FOXO3a exacerbated alveolitis and PF in rats and increased levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18.
CONCLUSIONS: miR-155-5p aggravated alveolitis and promoted PF by targeting FOXO3a and prompting the activation of NLRP3 inflammasome and then inducing IL-1β and IL-18 release.