LAMP3 induces ectopic TLR7 expression in salivary gland epithelial cells and amplifies type I IFN production in Sjögren's disease

Hiroyuki Nakamura; Tsutomu Tanaka; Changyu Zheng; Sandra A Afione; Tatsuya Atsumi; Masayuki Noguchi; Fabiola Reis Oliveira; Ana Carolina F Motta; Fernando Chahud; Eduardo M Rocha; Blake M Warner; John A Chiorini

doi:10.1002/art.42844

LAMP3 induces ectopic TLR7 expression in salivary gland epithelial cells and amplifies type I IFN production in Sjögren's disease

Arthritis Rheumatol. 2024 Mar 12. doi: 10.1002/art.42844. Online ahead of print.

Authors

Affiliations

¹ AAV Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
² Department of Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
³ Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
⁴ Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
⁵ Department of Clinical Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
⁶ Department of Stomatology, Public Health and Forensic Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
⁷ Department of Pathology and Forensic Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
⁸ Department of Ophthalmology, Otorhinolaryngology, Head and Neck Surgery, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
⁹ Salivary Disorder Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.

PMID: 38472139
DOI: 10.1002/art.42844

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 (TLR7) expression and type I IFN production in salivary gland epithelial cells both in vitro and in vivo. TLR7 knock-out 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 TLR7 expression in salivary gland epithelial cells. This positive feed-back 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.