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Amplified Type I Interferon Response in Sjögren's Disease via Ectopic Toll‐Like Receptor 7 Expression in Salivary Gland Epithelial Cells Induced by Lysosome‐Associated Membrane Protein 3.
- Source :
- Arthritis & Rheumatology; Jul2024, Vol. 76 Issue 7, p1109-1119, 11p
- Publication Year :
- 2024
-
Abstract
- Objective: Lysosome‐associated membrane protein 3 (LAMP3) misexpression in salivary gland epithelial cells plays a causal role in the development of salivary gland dysfunction and autoimmunity associated with Sjögren's disease (SjD). This study aimed to clarify how epithelial LAMP3 misexpression is induced in SjD. Methods: To explore upstream signaling pathways associated with LAMP3 expression, we conducted multiple RNA sequencing analyses of minor salivary glands from patients with SjD, submandibular glands from a mouse model of SjD, and salivary gland epithelial cell lines. A hypothesis generated by the RNA sequencing analyses was further tested by in vitro and in vivo assays with gene manipulation. Results: Transcriptome analysis suggested LAMP3 expression was associated with enhanced type I interferon (IFN) and IFNγ signaling pathways in patients with SjD. In vitro studies showed that type I IFN but not IFNγ stimulation could induce LAMP3 expression in salivary gland epithelial cells. Moreover, we discovered that LAMP3 overexpression could induce ectopic Toll‐like receptor 7 (TLR‐7) expression and type I IFN production in salivary gland epithelial cells both in vitro and in vivo. TLR‐7 knockout mice did not develop any SjD‐related symptoms following LAMP3 induction. Conclusion: Epithelial LAMP3 misexpression can be induced through enhanced type I IFN response in salivary glands. In addition, LAMP3 can promote type I IFN production via ectopic TLR‐7 expression in salivary gland epithelial cells. This positive feedback loop can contribute to maintaining LAMP3 misexpression and amplifying type I IFN production in salivary glands, which plays an essential role in the pathophysiology of SjD. [ABSTRACT FROM AUTHOR]
- Subjects :
- RNA analysis
EPITHELIAL cells
LYSOSOMES
BIOLOGICAL models
IN vitro studies
TOLL-like receptors
CELLULAR signal transduction
IN vivo studies
DESCRIPTIVE statistics
INTERFERONS
GENE expression
MICE
ANIMAL experimentation
GENE expression profiling
SJOGREN'S syndrome
SALIVARY glands
MEMBRANE proteins
SEQUENCE analysis
SYMPTOMS
Subjects
Details
- Language :
- English
- ISSN :
- 23265191
- Volume :
- 76
- Issue :
- 7
- Database :
- Complementary Index
- Journal :
- Arthritis & Rheumatology
- Publication Type :
- Academic Journal
- Accession number :
- 178161918
- Full Text :
- https://doi.org/10.1002/art.42844