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- Title
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.
- Authors
Nakamura, Hiroyuki; Tanaka, Tsutomu; Zheng, Changyu; Afione, Sandra A.; Atsumi, Tatsuya; Noguchi, Masayuki; Oliveira, Fabiola Reis; Motta, Ana Carolina F.; Chahud, Fernando; Rocha, Eduardo M.; Warner, Blake M.; Chiorini, John A.
- 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.
- 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
- Publication
Arthritis & Rheumatology, 2024, Vol 76, Issue 7, p1109
- ISSN
2326-5191
- Publication type
Article
- DOI
10.1002/art.42844