TGF-β/SMAD4 mediated UCP2 downregulation contributes to Aspergillus protease-induced inflammation in primary bronchial epithelial cells

Abstract

Elevated levels of mitochondrial reactive oxygen species (ROS) can lead to the development of airway inflammation. In this study, we investigated the role of Aspergillus proteases—which contribute to the pathogenesis of Aspergillus-induced diseases such as allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, and atopic asthma—and their mechanisms of action in airway inflammation using primary human bronchial epithelial cells, and evaluated the inflammatory responses mediated by mitochondrial ROS. We found that Aspergillus proteases regulated the expression of multifunctional inflammatory cytokines such as interleukin (IL)− 1β, − 6, and − 8, and transforming growth factor (TGF)-β, which stimulated cytokine production and chemokines involved in leukocyte migration and activated an inflammatory cascade. Expression of these factors and activator protein (AP)− 1 were decreased by treatment with the mitochondrial ROS scavenger Mito-TEMPO, suggesting that mitochondria are important sources of ROS in the context of inflammatory response by Aspergillus protease. The regulation of mitochondrial ROS influenced the production of proinflammatory mediators by preventing mitochondrial ROS-induced AP-1 activation in airway epithelial cells. In addition, Aspergillus protease-mediated mitochondrial ROS production was associated with downregulation of uncoupling protein (UCP)− 2 expression by TGF-β-SMAD4 signaling, which may play a regulatory role in mitochondrial ROS formation during fungal protease-mediated epithelial inflammation. This improved understanding of the allergenic fungal protease-induced inflammatory mechanism in the bronchial epithelium will help in developing intervention strategies for the regulation of inflammatory response in allergic airway diseases.

Effect of Estrogen on Heteronemin-Induced Anti-proliferative Effect in Breast Cancer Cells With Different Estrogen Receptor Status

“…The inhibitory effect of E 2 on UCP2 was further enhanced by heteronemin treatment ( Figure 5B ). Downregulation of UCP2 expression by TGF-β-SMAD4 signaling was shown to play a regulatory role in mitochondrial ROS formation ( Kim and Lee, 2018 ). Thus, heteronemin stimulated TGF-β1 expression to downregulate UCP expression and further increase ROS production in MCF-7 cells at 0.625 μM.…”

Transcriptomic analysis delineates potential signature genes and miRNAs associated with the pathogenesis of asthma

“…Our studies pointed out SMAD4 as a critical transcriptional factor involved in regulatory aspects of asthma pathogenesis. During fungal protease-mediated epithelial inflammation, downregulation of Uncoupling Protein 2 (UCP2) expression by regulatory TGF-β-SMAD4 signaling was associated with mitochondrial reactive oxygen species (ROS) production 41 . Based on our analysis, we identified mir-34b-5p and miR-449c-5p (members of the miR-34/449 family) as highest-ranked microRNAs involved in the regulation of FFL involving transcription factor SMAD4 and SERPINB2 hub gene in asthma.…”

“…Our studies pointed out SMAD4 as a critical transcriptional factor involved in regulatory aspects of asthma pathogenesis. During fungal protease-mediated epithelial inflammation, downregulation of Uncoupling Protein 2 (UCP2) expression by regulatory TGF- β -SMAD4 signaling was associated with mitochondrial reactive oxygen species (ROS) production 41 .…”

Serum from Asthmatic Mice Potentiates the Therapeutic Effects of Mesenchymal Stromal Cells in Experimental Allergic Asthma

“…This may be explained by the higher protease levels in BALF compared with serum from HDM mice (7.2 [6.2–7.9] and 2.9 [1.8–4], respectively) in baseline conditions. In allergic asthma, the BALF almost invariably contains significant quantities of proteases . MSCs present cell surface proteins, cell‐adhesion molecules, signaling receptors, transporters, receptors, and enzymes .…”