SEARCHOTHERophthalmology, preclinical research

other·ophthalmology, preclinical research, biomedical research, cataract surgery, ocular immunology·PMC10671722

Prdx6 Regulates Nlrp3 Inflammasome Activation-Driven Inflammatory Response in Lens Epithelial Cells

International Journal of Molecular Sciences · 5 authors, 2 centres

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TL;DR

Using Prdx6-knockout and aging mouse lens epithelial cells, this preclinical study shows that Prdx6 deficiency causes oxidative stress-driven Nlrp3 inflammasome activation and pyroptosis, and that delivering Prdx6 or silencing Klf9 prevents this inflammatory response.

Full summary

316 CHARS

Oxidative exposure further amplified ROS and increased Nlrp3 inflammasome pathway activation. Mechanistically, oxidative stress enhanced Kruppel-like factor 9 (Klf9) expression, leading to Klf9-dependent upregulation of Nlrp3 transcription. Delivery of Prdx6 or silencing of Klf9 prevented the inflammatory response.

STUDY TYPE

other

SPECIALTY

ophthalmology

SUMMARISED BY

AI pipeline

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100% · A

ORIGINAL PAPER

PMC10671722

Prdx6 Regulates Nlrp3 Inflammasome Activation-Driven Inflammatory Response in Lens Epithelial Cells

International Journal of Molecular Sciences

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ABSTRACT

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 Prdx6 -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 Prdx6 −/− 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/ Prdx6 −/− 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.

CITATION EXPORT

Bhavana Chhunchha, Rakesh Kumar, Eri Kubo et al.. Prdx6 Regulates Nlrp3 Inflammasome Activation-Driven Inflammatory Response in Lens Epithelial Cells. International Journal of Molecular Sciences. (2023). https://doi.org/10.3390/ijms242216276

AUTHORS

5 · 2 CENTRES

Bhavana Chhunchha, Rakesh Kumar, Eri Kubo, Priyanka Thakur, Dhirendra P. Singh

1Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA; [email protected] (R.K.); [email protected] (P.T.)
2Department of Ophthalmology, Kanazawa Medical University, Kahoku 9200293, Ishikawa, Japan; [email protected]

EDITOR / REVIEWER

Anna Perri