Endoplasmic Reticulum Stress and Unfolded Protein Response Sensor ERN1 Regulates Organic Dust Induction of Lung Inflammation
ABSTRACT Inhalation of organic dust increases the risk for respiratory symptoms and respiratory diseases, with chronic inflammation playing a major role in their development. Previously, we reported that organic dust induction of inflammatory mediators in bronchial epithelial cells is mediated throu...
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| Language: | English |
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Wiley
2025-07-01
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| Series: | FASEB BioAdvances |
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| Online Access: | https://doi.org/10.1096/fba.2025-00069 |
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| author | Shilpa Kusampudi Velmurugan Meganathan Vijay Boggaram |
| author_facet | Shilpa Kusampudi Velmurugan Meganathan Vijay Boggaram |
| author_sort | Shilpa Kusampudi |
| collection | DOAJ |
| description | ABSTRACT Inhalation of organic dust increases the risk for respiratory symptoms and respiratory diseases, with chronic inflammation playing a major role in their development. Previously, we reported that organic dust induction of inflammatory mediators in bronchial epithelial cells is mediated through increase of intracellular reactive oxygen species (ROS) and activation of NFκB and Stat3. Oxidative stress caused by increased ROS has been linked to the activation of endoplasmic reticulum (ER) stress and unfolded protein response (UPR). UPR modulates immune responses and plays key roles in the development of acute and chronic diseases. Herein, we hypothesized that organic dust‐induced ER stress‐UPR regulates airway epithelial cell inflammatory responses. We found that poultry organic dust extract (referred to as dust extract) increased the expression of ER stress/UPR sensor ERN1 in Beas2B bronchial epithelial cells. Dust extract was also found to increase ERN1 protein levels in mouse lungs with ERN1 immunostaining detected predominantly in the bronchial epithelium. Additionally, dust extract increased Ser724 ERN1 phosphorylation in the mouse bronchial epithelium indicating activation. Chemical inhibition and mRNA knockdown studies revealed that TLR2/TLR4‐Myd88‐ROS‐NFκB/Stat3 pathway mediates ERN1 induction. ERN1 chemical inhibitors, KIRA6 and APY29, and ERN1 mRNA knockdown reduced the induction of IL6, CXCL8, and pro IL1β. KIRA6 inhibited dust extract stimulation of NFκB‐p65, Stat3, Jun and MAPK 8/9 phosphorylation. Our studies have shown that ER stress and ERN1 are new players in the control of organic dust induced lung inflammation. Cross‐regulation between members of cell signaling cascade, TLR2‐TLR4/MyD88/ROS/ERN1/NFκB/Stat3 may fine tune immune and inflammatory responses elicited by organic dust. |
| format | Article |
| id | doaj-art-98b1cc31d0fc4ee0953b6102c74e893c |
| institution | Kabale University |
| issn | 2573-9832 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | FASEB BioAdvances |
| spelling | doaj-art-98b1cc31d0fc4ee0953b6102c74e893c2025-08-20T03:35:32ZengWileyFASEB BioAdvances2573-98322025-07-0177n/an/a10.1096/fba.2025-00069Endoplasmic Reticulum Stress and Unfolded Protein Response Sensor ERN1 Regulates Organic Dust Induction of Lung InflammationShilpa Kusampudi0Velmurugan Meganathan1Vijay Boggaram2Department of Cellular and Molecular Biology, Health Science Center University of Texas at Tyler Tyler Texas USADepartment of Cellular and Molecular Biology, Health Science Center University of Texas at Tyler Tyler Texas USADepartment of Cellular and Molecular Biology, Health Science Center University of Texas at Tyler Tyler Texas USAABSTRACT Inhalation of organic dust increases the risk for respiratory symptoms and respiratory diseases, with chronic inflammation playing a major role in their development. Previously, we reported that organic dust induction of inflammatory mediators in bronchial epithelial cells is mediated through increase of intracellular reactive oxygen species (ROS) and activation of NFκB and Stat3. Oxidative stress caused by increased ROS has been linked to the activation of endoplasmic reticulum (ER) stress and unfolded protein response (UPR). UPR modulates immune responses and plays key roles in the development of acute and chronic diseases. Herein, we hypothesized that organic dust‐induced ER stress‐UPR regulates airway epithelial cell inflammatory responses. We found that poultry organic dust extract (referred to as dust extract) increased the expression of ER stress/UPR sensor ERN1 in Beas2B bronchial epithelial cells. Dust extract was also found to increase ERN1 protein levels in mouse lungs with ERN1 immunostaining detected predominantly in the bronchial epithelium. Additionally, dust extract increased Ser724 ERN1 phosphorylation in the mouse bronchial epithelium indicating activation. Chemical inhibition and mRNA knockdown studies revealed that TLR2/TLR4‐Myd88‐ROS‐NFκB/Stat3 pathway mediates ERN1 induction. ERN1 chemical inhibitors, KIRA6 and APY29, and ERN1 mRNA knockdown reduced the induction of IL6, CXCL8, and pro IL1β. KIRA6 inhibited dust extract stimulation of NFκB‐p65, Stat3, Jun and MAPK 8/9 phosphorylation. Our studies have shown that ER stress and ERN1 are new players in the control of organic dust induced lung inflammation. Cross‐regulation between members of cell signaling cascade, TLR2‐TLR4/MyD88/ROS/ERN1/NFκB/Stat3 may fine tune immune and inflammatory responses elicited by organic dust.https://doi.org/10.1096/fba.2025-00069endoplasmic reticulum stressinflammationlungoxidative stressunfolded protein response |
| spellingShingle | Shilpa Kusampudi Velmurugan Meganathan Vijay Boggaram Endoplasmic Reticulum Stress and Unfolded Protein Response Sensor ERN1 Regulates Organic Dust Induction of Lung Inflammation FASEB BioAdvances endoplasmic reticulum stress inflammation lung oxidative stress unfolded protein response |
| title | Endoplasmic Reticulum Stress and Unfolded Protein Response Sensor ERN1 Regulates Organic Dust Induction of Lung Inflammation |
| title_full | Endoplasmic Reticulum Stress and Unfolded Protein Response Sensor ERN1 Regulates Organic Dust Induction of Lung Inflammation |
| title_fullStr | Endoplasmic Reticulum Stress and Unfolded Protein Response Sensor ERN1 Regulates Organic Dust Induction of Lung Inflammation |
| title_full_unstemmed | Endoplasmic Reticulum Stress and Unfolded Protein Response Sensor ERN1 Regulates Organic Dust Induction of Lung Inflammation |
| title_short | Endoplasmic Reticulum Stress and Unfolded Protein Response Sensor ERN1 Regulates Organic Dust Induction of Lung Inflammation |
| title_sort | endoplasmic reticulum stress and unfolded protein response sensor ern1 regulates organic dust induction of lung inflammation |
| topic | endoplasmic reticulum stress inflammation lung oxidative stress unfolded protein response |
| url | https://doi.org/10.1096/fba.2025-00069 |
| work_keys_str_mv | AT shilpakusampudi endoplasmicreticulumstressandunfoldedproteinresponsesensorern1regulatesorganicdustinductionoflunginflammation AT velmuruganmeganathan endoplasmicreticulumstressandunfoldedproteinresponsesensorern1regulatesorganicdustinductionoflunginflammation AT vijayboggaram endoplasmicreticulumstressandunfoldedproteinresponsesensorern1regulatesorganicdustinductionoflunginflammation |