Polymeric immunoglobulin receptor (pIgR) is one important player of mucosal defenses, but very little is known on pIgR-mediated immune excretion of the antigens that penetrate mucosal surface in fish. Previously, we cloned the pIgR of flounder (Paralichthys olivaceus) and developed anti-pIgR antibody. In this study, the flounders were immunized intraperitoneally with the chicken ovalbumin (OVA) and the control protein bovine serum albumin (BSA) to elicit mucosal IgM antibody and pIgR response, and then challenged with OVA via caudal vein injection after the immunized OVA was absent from fish body at the fourth week after immunization. After OVA challenge, strong OVA-positive fluorescence signals were observed in lamina propria (LP) submucosa and epithelial cells of the hindgut at 30 min, increased proceeding toward the distal portion of intestinal folds, reached a peak at 2–3 h, and then weakened and disappeared at 12 h, indicating that the OVA rapidly diffused from bloodstream into LP submucosa and excreted across intestinal epithelium. Whereas in BSA-immunized and OVA-challenged control fish, the OVA was detected in LP submucosa but not in intestinal epithelium due to the lack of OVA-specific antibody. Accordingly, in intestinal epithelium, the transepithelial transport of OVA was confirmed by immunogold electron microscopy, and co-localization of OVA, IgM, and pIgR was illuminated by multiple-label immunofluorescence confocal microscopy and analyzed using Image J software. Furthermore, in gut mucus but not in serum, an ~800-kDa protein band showed IgM-positive, OVA-positive, and pIgR-positive simultaneously, and the OVA, together with IgM and secretory component (SC) of pIgR, could be immunoprecipitated by anti-OVA antibody, demonstrating the existence of SC–polymeric IgM–OVA complexes. All these results collectively revealed that the pIgR could transport mucosal IgM–OVA complexes from LP across intestinal epithelium into gut mucus via the transcytosis in flounder. These new findings provided direct evidences for pIgR-mediated immune excretion of IgM–antigen complexes, and better understanding the role of pIgR in mucosal immunity in teleost fish.

A well-established role of cyclic GMP-AMP synthase (cGAS) is the recognition of cytosolic DNA, which is linked to the activation of host defense programs against pathogens via stimulator of interferon genes (STING)-dependent innate immune response. Recent advance has also revealed that cGAS may be involved in several noninfectious contexts by localizing to subcellular compartments other than the cytosol. However, the subcellular localization and function of cGAS in different biological conditions is unclear; in particular, its role in cancer progression remains poorly understood. Here we show that cGAS is localized to mitochondria and protects hepatocellular carcinoma cells from ferroptosis in vitro and in vivo. cGAS anchors to the outer mitochondrial membrane where it associates with dynamin-related protein 1 (DRP1) to facilitate its oligomerization. In the absence of cGAS or DRP1 oligomerization, mitochondrial ROS accumulation and ferroptosis increase, inhibiting tumor growth. Collectively, this previously unrecognized role for cGAS in orchestrating mitochondrial function and cancer progression suggests that cGAS interactions in mitochondria can serve as potential targets for new cancer interventions.

Background Chronic obstructive pulmonary disease (COPD), characterized by persistent airflow limitation, was a disease mediated by a combination of inflammatory factors, immune cells, and immune mediators. COPD was an inflammatory and autoimmune disease involving T‐lymphocytes triggered by cigarette smoke and other factors that progressively affected the bronchi, lung parenchyma, and pulmonary blood vessels. LncRNAs were reported to be implicated in COPD pathogenesis and development. Methods Non‐smokers, smokers (non‐COPD), and COPD patients were randomly selected in an established COPD surveillance cohort. Demographic and clinical information of all subjects were collected. Pulmonary function was measured by post‐bronchodilator testing. qRT‐PCR and ELISA assays were performed to detect the expression levels of lncRNA LUCAT1, miR‐181a‐5p, and inflammatory cytokines. An in vitro exposure model was constructed using cigarette smoke extract (CSE)‐induced human bronchial epithelial (16HBE) cells. The dual‐luciferase reporter and RNA pull‐down assays were used to detect the binding relationship between lncRNA LUCAT1 and miR‐181a‐5p; meanwhile, Spearman's correlation assay was used to verify the correlation between lncRNA LUCAT1 and miR‐181a‐5p. Afterward, the lncRNA LUCAT1 silencing plasmid was constructed and co‐transfected with a miR‐181a‐5p inhibitor to evaluate the effects on CSE‐induced 16HBE cell proliferation and apoptosis. Finally, a Western blot assay was utilized to determine the mechanism of lncRNA LUCAT1/miR‐181a‐5p/Wnt/β‐catenin axis in COPD. Results LncRNA LUCAT1 was upregulated in the serums of COPD patients. Correlation analysis further confirmed the strong correlation between LUCAT1 expression and inflammatory cytokines IL‐1β, IL‐6, and TNF‐α. Receiver operating characteristic (ROC) analysis verified the potential of LUCAT1 in COPD diagnosis. After treatment with CSE, LUCAT1 was significantly increased while its target miR‐181a‐5p was decreased in 16HBE cells. Cell proliferation and apoptosis assays showed that LUCAT1 silencing alleviated CSE’s effects on 16HBE cell proliferation and apoptosis. Mechanically, rescue assays demonstrated that miR‐181a‐5p inhibition could partially counteract the impact of LUCAT1 on COPD progression through the Wnt/β‐catenin pathway. Conclusions LncRNA LUCAT1 may be a valuable indicator for differentiating COPD. Moreover, LncRNA LUCAT1/miR‐181‐5p/Wnt/β‐catenin axis behaved as a critical role in COPD development, shedding new sights for clinical treatment.

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