Dataset Information

LAMP3-associated extracellular vesicles induce apoptosis in Sjögren’s disease

ABSTRACT: Sjögren’s disease (SjD) is an autoimmune disease that affects exocrine tissues and is characterized by increased apoptosis and decreased expression of membrane proteins involved in secretory function, such as Na-K-Cl cotransporter-1 (NKCC1), in salivary and lacrimal glands. Although the pathogenic mechanism triggering SjD is not well understood, overexpression of lysosome-associated membrane protein 3 (LAMP3) is associated with the disease in a subset of SjD patients and the development of SjD-like phenotype in mice. In this study, histological analysis of minor salivary glands of SjD patients suggested that LAMP3-containing material is being ejected from cells. Follow-on in vitro experiments with cells exposed to larger extracellular vesicles (LEVs) derived from LAMP3-overexpressing cells showed increased apoptosis and decreased NKCC1 expression. Proteomics identified LAMP3 as a major component of LEVs derived from LAMP3-overexpressing cells. Live-cell imaging visualized release and uptake of LAMP3-containing LEVs from LAMP3-overexpressing cells to naïve cells. Furthermore, experiments with recombinant LAMP3 protein alone or complexed with Xfect protein transfection reagent demonstrated that internalization of LAMP3 was required for apoptosis in a caspase-dependent pathway. Taken together, we identified a new role for extracellular LAMP3 in cell-to-cell communication via LEVs, which provides further support for targeting LAMP3 as a therapeutic approach in SjD.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Sjogren's Syndrome

SUBMITTER: Yan Wang

LAB HEAD: Yan Wang

PROVIDER: PXD036774 | Pride | 2023-03-10

REPOSITORIES: pride

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LAMP3 transfer via extracellular particles induces apoptosis in Sjögren's disease.

Tanaka Tsutomu T Nakamura Hiroyuki H Tran Duy T DT Warner Blake M BM Wang Yan Y Atsumi Tatsuya T Noguchi Masayuki M Chiorini John A JA

Scientific reports 20230214 1

Sjögren's disease (SjD) is an autoimmune disease that affects exocrine tissues and is characterized by increased apoptosis in salivary and lacrimal glands. Although the pathogenic mechanism triggering SjD is not well understood, overexpression of lysosome-associated membrane protein 3 (LAMP3) is associated with the disease in a subset of SjD patients and the development of SjD-like phenotype in mice. In this study, histological analysis of minor salivary glands of SjD patients suggested that LAM ...[more]

PMID: 36788255

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Project description:Primary Sjögren’s syndrome (SS or autoimmune epithelitis) is a relatively common autoimmune disorder that is primarily characterized by chronic lymphoepithelial inflammatory reactions in the exocrine glands, mainly the salivary and lachrymal glands. It may extend from disease confined to the exocrine glands (organ-specific exocrinopathy) to various extraglandular manifestations (systemic disease) and the development of B-cell lymphoma. Several studies from our laboratory had provided evidence for the strong implication of ductal salivary gland epithelial cells (SGEC) in the pathogenesis of Sjögren’s syndrome (SS), including the development of salivary gland infiltrating lesions and of adverse systemic clinical complications, such as the development of B-cell lymphoma. In fact, the comparative assessment of non-neoplastic SGEC lines derived from SS patients and disease controls had indicated that the ductal epithelia of SS patients manifest an “intrinsically activated” status that is associated with distinct aberrant phenotypic and functional features encountered in “inflamed” cells. Herein, using microarray analysis, we sought to comparatively analyze the constitutive gene expression in long-term cultured non-neoplastic SGEC lines derived from non-SS sicca control individuals and from SS patients. The study aimed to reveal the genes that are differentially expressed between SGEC lines derived from SS patients and controls, as well as between SGEC lines derived from SS patients with moderate lymphocytic infiltrations (focus score<2; SS-Group-1) and SS patients with severe lymphocytic infiltrations (focus score ≥2; SS-Group-2). The transcriptome profiling analysis presented herein lends further support to the intrinsic activation status of patients’ ductal epithelia and its association with distinct proinflammatory and metabolism-related gene signatures, which occur primarily among patients with heavy tissue infiltrates and high risk for lymphoma development.

			Action	DRS
	2019_0903Chiorini01.msf	Msf
	2019_0903Chiorini01.raw	Raw
	2019_0903Chiorini02.msf	Msf
	2019_0903Chiorini02.raw	Raw
	2019_0903Chiorini03.msf	Msf