Prdx6 Regulates Nlrp3 Inflammasome Activation-Driven Inflammatory Response in Lens Epithelial Cells
The continuum of antioxidant response dysregulation in aging/oxidative stress-driven Nlrp3 inflammasome activation-mediated inflammatory response is associated with age-related diseases. Peroxiredoxin (Prdx) 6 is a key antioxidant that provides cytoprotection by regulating redox homeostasis. Herein,...
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| Format: | Article |
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MDPI AG
2023-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/22/16276 |
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| author | Bhavana Chhunchha Rakesh Kumar Eri Kubo Priyanka Thakur Dhirendra P. Singh |
| author_facet | Bhavana Chhunchha Rakesh Kumar Eri Kubo Priyanka Thakur Dhirendra P. Singh |
| author_sort | Bhavana Chhunchha |
| collection | DOAJ |
| description | The continuum of antioxidant response dysregulation in aging/oxidative stress-driven Nlrp3 inflammasome activation-mediated inflammatory response is associated with age-related diseases. Peroxiredoxin (Prdx) 6 is a key antioxidant that provides cytoprotection by regulating redox homeostasis. Herein, using lens epithelial cells (LECs) derived from the targeted inactivation of Prdx6 gene and aging lenses, we present molecular evidence that <i>Prdx6</i>-deficiency causes oxidative-driven Nlrp3 inflammasome activation, resulting in pyroptosis in aging/redox active cells wherein Prdx6 availability offsets the inflammatory process. We observed that <i>Prdx6</i><sup>−/−</sup> and aging LECs harboring accumulated reactive oxygen species (ROS) showed augmented activation of Nlrp3 and bioactive inflammatory components, like Caspase-1, IL-1β, ASC and Gasdermin-D. Similar to lipopolysaccharide treatment, oxidative exposure led to further ROS amplification with increased activation of the Nlrp3 inflammasome pathway. Mechanistically, we found that oxidative stress enhanced Kruppel-like factor 9 (Klf9) expression in aging/<i>Prdx6</i><sup>−/−</sup> mLECs, leading to a Klf9-dependent increase in Nlrp3 transcription, while the elimination of ROS by the delivery of Prdx6 or by silencing Klf9 prevented the inflammatory response. Altogether, our data identify the biological significance of Prdx6 as an intrinsic checkpoint for regulating the cellular health of aging or redox active LECs and provide opportunities to develop antioxidant-based therapeutic(s) to prevent oxidative/aging-related diseases linked to aberrant Nlrp3 inflammasome activation. |
| first_indexed | 2024-03-09T16:46:16Z |
| format | Article |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T16:46:16Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ca2d2c1a7468446cbe02cd384672f9392023-11-24T14:46:56ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-11-0124221627610.3390/ijms242216276Prdx6 Regulates Nlrp3 Inflammasome Activation-Driven Inflammatory Response in Lens Epithelial CellsBhavana Chhunchha0Rakesh Kumar1Eri Kubo2Priyanka Thakur3Dhirendra P. Singh4Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Ophthalmology, Kanazawa Medical University, Kahoku 9200293, Ishikawa, JapanDepartment of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USAThe continuum of antioxidant response dysregulation in aging/oxidative stress-driven Nlrp3 inflammasome activation-mediated inflammatory response is associated with age-related diseases. Peroxiredoxin (Prdx) 6 is a key antioxidant that provides cytoprotection by regulating redox homeostasis. Herein, using lens epithelial cells (LECs) derived from the targeted inactivation of Prdx6 gene and aging lenses, we present molecular evidence that <i>Prdx6</i>-deficiency causes oxidative-driven Nlrp3 inflammasome activation, resulting in pyroptosis in aging/redox active cells wherein Prdx6 availability offsets the inflammatory process. We observed that <i>Prdx6</i><sup>−/−</sup> and aging LECs harboring accumulated reactive oxygen species (ROS) showed augmented activation of Nlrp3 and bioactive inflammatory components, like Caspase-1, IL-1β, ASC and Gasdermin-D. Similar to lipopolysaccharide treatment, oxidative exposure led to further ROS amplification with increased activation of the Nlrp3 inflammasome pathway. Mechanistically, we found that oxidative stress enhanced Kruppel-like factor 9 (Klf9) expression in aging/<i>Prdx6</i><sup>−/−</sup> mLECs, leading to a Klf9-dependent increase in Nlrp3 transcription, while the elimination of ROS by the delivery of Prdx6 or by silencing Klf9 prevented the inflammatory response. Altogether, our data identify the biological significance of Prdx6 as an intrinsic checkpoint for regulating the cellular health of aging or redox active LECs and provide opportunities to develop antioxidant-based therapeutic(s) to prevent oxidative/aging-related diseases linked to aberrant Nlrp3 inflammasome activation.https://www.mdpi.com/1422-0067/24/22/16276oxidative stressPeroxiredoxin 6NF-ĸBNlrp3GSDMDCaspase-1 |
| spellingShingle | Bhavana Chhunchha Rakesh Kumar Eri Kubo Priyanka Thakur Dhirendra P. Singh Prdx6 Regulates Nlrp3 Inflammasome Activation-Driven Inflammatory Response in Lens Epithelial Cells International Journal of Molecular Sciences oxidative stress Peroxiredoxin 6 NF-ĸB Nlrp3 GSDMD Caspase-1 |
| title | Prdx6 Regulates Nlrp3 Inflammasome Activation-Driven Inflammatory Response in Lens Epithelial Cells |
| title_full | Prdx6 Regulates Nlrp3 Inflammasome Activation-Driven Inflammatory Response in Lens Epithelial Cells |
| title_fullStr | Prdx6 Regulates Nlrp3 Inflammasome Activation-Driven Inflammatory Response in Lens Epithelial Cells |
| title_full_unstemmed | Prdx6 Regulates Nlrp3 Inflammasome Activation-Driven Inflammatory Response in Lens Epithelial Cells |
| title_short | Prdx6 Regulates Nlrp3 Inflammasome Activation-Driven Inflammatory Response in Lens Epithelial Cells |
| title_sort | prdx6 regulates nlrp3 inflammasome activation driven inflammatory response in lens epithelial cells |
| topic | oxidative stress Peroxiredoxin 6 NF-ĸB Nlrp3 GSDMD Caspase-1 |
| url | https://www.mdpi.com/1422-0067/24/22/16276 |
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