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other·ophthalmology, dry eye, preclinical research, immunology, biomedical research·PMC10001612

Lacrimal Gland Epithelial Cells Shape Immune Responses through the Modulation of Inflammasomes and Lipid Metabolism

International Journal of Molecular Sciences · 9 authors, 4 centres

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TL;DR

This preclinical study used mouse models to show that lacrimal gland epithelial cells activate inflammasomes and alter lipid metabolism during acute and chronic inflammation, which may contribute to the pathogenesis of Sjögren's syndrome-like disease.

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BACKGROUND

Chronic lacrimal gland inflammation is a primary cause of aqueous-deficient dry eye, as seen in Sjögren's syndrome (SS). Inflammasome activation is implicated in autoimmune disorders, but its role and potential regulators in lacrimal gland epithelial cells are not fully understood. Methods: Researchers used mouse models: acute inflammation was induced by LPS/nigericin or IL-1α injection into the lacrimal gland; chronic inflammation was studied in two SS models, NOD.H2^b^ and Thrombospondin-1-null (TSP-1^-/-^) mice, compared to healthy controls. Inflammasome activation was assessed via immunostaining (using R26^ASC-citrine^ reporter mice), Western blot, and RNA sequencing. Key Results: Both acute and chronic inflammation activated multiple inflammasome sensors (e.g., AIM2, NLRP3, PYRIN) and upregulated caspases 1/4 and interleukins Il1b and Il18 in lacrimal gland epithelial cells. Increased IL-1β maturation was observed in the SS models. RNA-seq revealed that during resolution of acute injury, lipogenic genes were upregulated. In chronically inflamed NOD.H2^b^ glands, disease progression was associated with an altered lipid metabolism: upregulation of cholesterol metabolism genes and downregulation of mitochondrial and fatty acid synthesis genes, including PPARα/SREBP-1-dependent signaling. Implications: The results suggest that dysregulated inflammasome activation and lipid metabolism in epithelial cells are key drivers of SS-like pathogenesis in these models. This points to potential therapeutic avenues, such as targeting epithelial cell homeostasis alongside anti-inflammatory treatments.

STUDY TYPE

other

SPECIALTY

ophthalmology

SUMMARISED BY

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ORIGINAL PAPER

PMC10001612

Lacrimal Gland Epithelial Cells Shape Immune Responses through the Modulation of Inflammasomes and Lipid Metabolism

International Journal of Molecular Sciences

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ABSTRACT

Lacrimal gland inflammation triggers dry eye disease through impaired tear secretion by the epithelium. As aberrant inflammasome activation occurs in autoimmune disorders including Sjögren’s syndrome, we analyzed the inflammasome pathway during acute and chronic inflammation and investigated its potential regulators. Bacterial infection was mimicked by the intraglandular injection of lipopolysaccharide (LPS) and nigericin, known to activate the NLRP3 inflammasome. Acute injury of the lacrimal gland was induced by interleukin (IL)-1α injection. Chronic inflammation was studied using two Sjögren’s syndrome models: diseased NOD.H2 b compared to healthy BALBc mice and Thrombospondin-1-null (TSP-1 -/- ) compared to TSP-1 WT C57BL/6J mice. Inflammasome activation was investigated by immunostaining using the R26 ASC-citrine reporter mouse, by Western blotting, and by RNAseq. LPS/Nigericin, IL-1α and chronic inflammation induced inflammasomes in lacrimal gland epithelial cells. Acute and chronic inflammation of the lacrimal gland upregulated multiple inflammasome sensors, caspases 1/4, and interleukins Il1b and Il18 . We also found increased IL-1β maturation in Sjögren’s syndrome models compared with healthy control lacrimal glands. Using RNA-seq data of regenerating lacrimal glands, we found that lipogenic genes were upregulated during the resolution of inflammation following acute injury. In chronically inflamed NOD.H2 b lacrimal glands, an altered lipid metabolism was associated with disease progression: genes for cholesterol metabolism were upregulated, while genes involved in mitochondrial metabolism and fatty acid synthesis were downregulated, including peroxisome proliferator-activated receptor alpha (PPARα)/sterol regulatory element-binding 1 (SREBP-1)-dependent signaling. We conclude that epithelial cells can promote immune responses by forming inflammasomes, and that sustained inflammasome activation, together with an altered lipid metabolism, are key players of Sjögren’s syndrome-like pathogenesis in the NOD.H2 b mouse lacrimal gland by promoting epithelial dysfunction and inflammation.

CITATION EXPORT

Vanessa Delcroix, Olivier Mauduit, Menglu Yang et al.. Lacrimal Gland Epithelial Cells Shape Immune Responses through the Modulation of Inflammasomes and Lipid Metabolism. International Journal of Molecular Sciences. (2023). https://doi.org/10.3390/ijms24054309

AUTHORS

9 · 4 CENTRES

Vanessa Delcroix, Olivier Mauduit, Menglu Yang, Amrita Srivastava, Takeshi Umazume, Cintia S. de Paiva, Valery I. Shestopalov, Darlene A. Dartt, Helen P. Makarenkova

1Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
2Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
3The Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA
4Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL 33136, USA

EDITOR / REVIEWER

Mariarosaria Boccellino