LncRNA MIAT suppresses inflammation in LPS-induced J774A.1 macrophages by promoting autophagy through miR-30a-5p/SOCS1 axi.

Accumulated data implicate that long noncoding RNA (lncRNA) plays a pivotal role in rheumatoid arthritis (RA), potentially serving as a competitive endogenous RNA (ceRNA) for microRNAs (miRNAs). The lncRNA myocardial infarction-associated transcript (MIAT) has been demonstrated to regulate inflammation. However, the role of MIAT in the inflammation of RA remains inadequately explored. This study aims to elucidate MIAT's role in the inflammation of lipopolysaccharide (LPS)-induced macrophages and to uncover the underlying molecular mechanisms. We observed heightened MIAT expression in LPS-induced J774A.1 cells and collagen-induced arthritis mouse models, in contrast to the expression pattern of miR-30a-5p. Silencing MIAT resulted in increased expression of the inflammatory cytokines IL-1ß and TNF-α. Simultaneously, MIAT interference significantly impeded macrophage autophagy, evidenced by decreased expression of autophagy-related markers LC3-II and Beclin-1, alongside increased levels of p62 in LPS-induced J774A.1 cells. Notably, MIAT functioned as a ceRNA, sponging miR-30a-5p and exerting a negative regulatory influence on its expression. SOCS1 emerged as a target of miR-30a-5p, modulated by MIAT. Mechanistically, inhibiting miR-30a-5p reversed the impact of MIAT deficiency in promoting LPS-induced inflammation, while SOCS1 knockdown countered the cytokine inhibitory effect induced by silencing miR-30a-5p. In summary, this study indicates that lncRNA MIAT suppresses inflammation in LPS-induced J774A.1 macrophages by stimulating autophagy through the miR-30a-5p/SOCS1 axis. This suggests that MIAT holds promise as a potential therapeutic target for RA inflammation.

Inhibition of NEMO alleviates arthritis by blocking the M1 macrophage polarization.

The nuclear factor-kappa B (NF-κB) signaling pathway and macrophages are critically involved in the pathogenesis of rheumatoid arthritis (RA). Recent studies have identified NF-κB essential modulator (NEMO), a regulatory subunit of the inhibitor of NF-κB kinase (IKK), as a potential target to inhibit NF-κB signaling pathway. Here, we investigated the interactions between NEMO and M1 macrophage polarization in RA. NEMO inhibition led to the suppression of proinflammatory cytokines secreted from M1 macrophages in collagen-induced arthritis mice. From lipopolysaccharide (LPS)-stimulated RAW264, knocking down NEMO blocked M1 macrophage polarization accompanied by lesser M1 proinflammatory subtype. Our findings link the novel regulatory component of NF-κB signaling and human arthritis pathologies which will pave the way towards the identification of new therapeutic targets and the development of innovative preventive strategies.

Iguratimod ameliorates bleomycin-induced pulmonary fibrosis by inhibiting the EMT process and NLRP3 inflammasome activation.

BACKGROUND: Pulmonary fibrosis is the deadliest manifestation of connective tissue disease (CTD). Iguratimod (IGU) is a new drug that is used for controlling CTD. Clinical studies have found that IGU has certain advantages in improving lung function and shows great potential for pulmonary fibrosis therapy. However, the specific mechanism is not clear. This study was designed to observe and investigate the therapeutic effects of IGU on bleomycin-induced pulmonary fibrosis and further investigate its underlying mechanism. METHODS: A mouse model of pulmonary fibrosis was induced by intratracheal injection of bleomycin (BLM). Model mice were randomly assigned to receive different concentrations of IGU. A TGF-ß (T)-induced A549 epithelial-mesenchymal transition (EMT) cell model was utilized to investigate the effects of IGU on EMT in vitro. The NLRP3 inflammasome was activated by the costimulation of LPS+ATP (LA) to evaluate the effects of IGU in vitro. RESULTS: We found that IGU resulted in favourable therapeutic outcomes by affecting inflammatory infiltration and collagen deposition. Additionally, the markers of the BLM-mediated EMT phenotype and NLRP3-activated phenotype in the lung were also attenuated after IGU administration. In vitro experiments, the results confirmed its anti-EMT and anti-NLRP3 inflammasome activation effects.We then found that the anti-lung fibrosis effect of IGU was accompanied by a decrease in reactive oxygen species (ROS) production. CONCLUSION: IGU can inhibit the EMT process and NLRP3 inflammasome activation and reduce ROS production to ameliorate pulmonary fibrosis, which may provide new insights into the further application of IGU in interstitial pulmonary fibrosis.

IL-17A Promotes the Migration, Invasion and the EMT Process of Lung Cancer Accompanied by NLRP3 Activation.

Background: Lung cancer is a deadly cancer worldwide, and its pathogenesis and treatment methods require continuous research and exploration. As a representative factor of adaptive immunity, the role of interleukin-17A (IL-17A) in lung cancer is still unclear. The purpose of the present study was to investigate the effect of IL-17A on the biological behaviour of lung cancer cells and the relative mechanism. Methods: The human lung adenocarcinoma A549 and H1299 cell lines were used for in vitro study. The effects of IL-17A on cell proliferation, migration and invasion were assessed by CCK-8 assay, wound-healing assay, transwell invasion assay and real-time cell analysis (RTCA). The expression levels of marker proteins in the process of epithelial-mesenchymal transition (EMT) were detected by western blot analysis. Caspase-1 activity and the concentration of IL-1ß after NLRP3 inflammasome activation were measured by a Caspase-1 Activity Assay Kit and an IL-1ß ELISA kit, respectively. Results: Compared to the control group, IL-17A treatment did not affect the proliferation of A549 and H1299 cells in vitro, but it promoted cell migration, invasion and the EMT process. IL-17A treatment increased NLRP3 expression, caspase-1 activity and IL-1ß level. Blockade of NLRP3 alleviated the cell migration, invasion and the EMT process induced by IL-17A. Conclusions: In conclusion, these findings indicated that NLRP3 participates in the migration, invasion and the EMT process of IL-17A-stimulated lung cells in vitro.

IL-6 promotes collagen-induced arthritis by activating the NLRP3 inflammasome through the cathepsin B/S100A9-mediated pathway.

Rheumatoid arthritis (RA) is an inflammatory disease with symmetric polyarthritis. IL-6 and NLRP3 inflammasome in macrophages contribute to the pathogenesis of RA. This study aimed to investigate the relationship between IL-6 and the NLRP3 inflammasome in RA. Here, we found that IL-6 inhibition reduced NLRP3 inflammasome activation in mice with collage-induced arthritis (CIA). In vitro studies showed that IL-6 directly induced NLRP3 inflammasome activation via cathepsin B (CTSB) in the presence of ATP. In addition, S100A9 induced by ATP stimulation promoted the interaction of CTSB and NLRP3 to activate the NLRP3 inflammasome. Our findings show a novel mechanism of NLRP3 inflammasome activation by IL-6 that may lead to a potential therapy for RA by interrupting the interaction between IL-6 and the NLRP3 inflammasome.