Targeting alarmin release reverses Sjogren's syndrome phenotype by revitalizing Ca 2+ signalling.

Autor: Sun Y; Department of Periodontics, School of Dentistry, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA., Nascimento Da Conceicao V; Department of Periodontics, School of Dentistry, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA., Chauhan A; Department of Developmental Dentistry, School of Dentistry, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA., Sukumaran P; Department of Periodontics, School of Dentistry, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA., Chauhan P; Department of Developmental Dentistry, School of Dentistry, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA., Ambrus JL; Division of Allergy, Immunology, and Rheumatology, Department of Medicine, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York, USA., Vissink A; Department of Oral and Maxillofacial Surgery, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands., Kroese FGM; Department of Rheumatology and Clinical Immunology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands., Muniswamy M; Department of Medicine, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA., Mishra BB; Department of Developmental Dentistry, School of Dentistry, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA.; Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA., Singh BB; Department of Periodontics, School of Dentistry, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA.
Jazyk: angličtina
Zdroj: Clinical and translational medicine [Clin Transl Med] 2023 Apr; Vol. 13 (4), pp. e1228.
DOI: 10.1002/ctm2.1228
Abstrakt: Background: Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease that is embodied by the loss of salivary gland function and immune cell infiltration, but the mechanism(s) are still unknown. The aim of this study was to understand the mechanisms and identify key factors that leads to the development and progression of pSS.
Methods: Immunohistochemistry staining, FACS analysis and cytokine levels were used to detect immune cells infiltration and activation in salivary glands. RNA sequencing was performed to identify the molecular mechanisms involved in the development of pSS. The function assays include in vivo saliva collection along with calcium imaging and electrophysiology on isolated salivary gland cells in mice models of pSS. Western blotting, real-time PCR, alarmin release, and immunohistochemistry was performed to identify the channels involved in salivary function in pSS.
Results: We provide evidence that loss of Ca 2+ signaling precedes a decrease in saliva secretion and/or immune cell infiltration in IL14α, a mouse model for pSS. We also showed that Ca 2+ homeostasis was mediated by transient receptor potential canonical-1 (TRPC1) channels and inhibition of TRPC1, resulting in the loss of salivary acinar cells, which promoted alarmin release essential for immune cell infiltration/release of pro-inflammatory cytokines. In addition, both IL14α and samples from human pSS patients showed a decrease in TRPC1 expression and increased acinar cell death. Finally, paquinimod treatment in IL14α restored Ca 2+ homeostasis that inhibited alarmin release thereby reverting the pSS phenotype.
Conclusions: These results indicate that loss of Ca 2+ signaling is one of the initial factors, which induces loss of salivary gland function along with immune infiltration that exaggerates pSS. Importantly, restoration of Ca 2+ signaling upon paquinimod treatment reversed the pSS phenotype thereby inhibiting the progressive development of pSS.
(© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
Databáze: MEDLINE
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