| Autor: |
Mo YQ; AAV Biology Section and., Nakamura H; AAV Biology Section and., Tanaka T; AAV Biology Section and., Odani T; AAV Biology Section and., Perez P; AAV Biology Section and.; Salivary Disorder Unit, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland, USA., Ji Y; AAV Biology Section and., French BN; AAV Biology Section and., Pranzatelli TJ; AAV Biology Section and., Michael DG; AAV Biology Section and., Yin H; AAV Biology Section and., Chow SS; AAV Biology Section and., Khalaj M; AAV Biology Section and., Afione SA; AAV Biology Section and., Zheng C; AAV Biology Section and., Oliveira FR; Department of Clinical Medicine, Ribeirão Preto Medical School., Motta ACF; Department of Stomatology, Public Health and Forensic Dentistry, School of Dentistry of Ribeirão Preto., Ribeiro-Silva A; Department of Pathology and Legal Medicine, Ribeirão Preto Medical School, and., Rocha EM; Department of Ophthalmology, Otorhinolaryngology, Head and Neck Surgery, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil., Nguyen CQ; Department of Pathology and Infectious Diseases, University of Florida, Gainesville, Florida, USA., Noguchi M; Division of Cancer Biology, Institute for Genetic Medicine and., Atsumi T; Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine, Hokkaido University, Sapporo, Japan., Warner BM; AAV Biology Section and.; Salivary Disorder Unit, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland, USA., Chiorini JA; AAV Biology Section and. |
| Abstrakt: |
BMP6 is a central cytokine in the induction of Sjögren's syndrome-associated (SS-associated) secretory hypofunction. However, the upstream initiation leading to the production of this cytokine in SS is unknown. In this study, RNA ISH on salivary gland sections taken from patients with SS indicated monocytic lineage cells as a cellular source of BMP6. RNA-Seq data on human salivary glands suggested that TLR4 signaling was an upstream regulator of BMP6, which was confirmed by in vitro cell assays and single-cell transcriptomics of human PBMCs. Further investigation showed that HSP70 was an endogenous natural TLR4 ligand that stimulated BMP6 expression in SS. Release of HSP70 from epithelial cells could be triggered by overexpression of lysosome-associated membrane protein 3 (LAMP3), a protein also associated with SS in several transcriptome studies. In vitro studies supported the idea that HSP70 was released as a result of lysosomal exocytosis initiated by LAMP3 expression, and reverse transcription PCR on RNA from minor salivary glands of patients with SS confirmed a positive correlation between BMP6 and LAMP3 expression. BMP6 expression could be experimentally induced in mice by overexpression of LAMP3, which developed an SS-like phenotype. The newly identified LAMP3/HSP70/BMP6 axis provided an etiological model for SS gland dysfunction and autoimmunity. |
