biostudies-literatureMo YQIntramural NIH HHSNIDCR NIH HHSConselho Nacional de Desenvolvimento Científico e TecnológicoNIDCD NIH HHSNIH intramural research grantResearch Core of Ocular Physiopathology and Therapeutics of the University of São PauloSão Paulo Research Foundation FAPESPe152780https://www.ebi.ac.uk/biostudies/studies/S-EPMC8920330biostudies-literatureUnknown132(6)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 proteiThe Journal of clinical investigationLysosomal exocytosis of HSP70 stimulates monocytic BMP6 expression in Sjogren's syndrome.PMC8920330R01 DC000086ZIA DE000695ZIG DE0007401ZIADE000704302355/2017-0ZIA DE000704R01 DE028544ZIC DE00075012.1.25431.01.71ZIADE0006952014/23211-0,2014/22451-7ZIC DC000086Odani TPerez PAfione SAMotta ACFRocha EMNguyen CQPranzatelli TJAtsumi TMo YQNakamura HWarner BMNoguchi MChiorini JAOliveira FRYin HTanaka TMichael DGZheng CJi YFrench BNKhalaj MRibeiro-Silva AChow SSfalseLysosomal exocytosis of HSP70 stimulates monocytic BMP6 expression in Sjogren's syndrome.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 protei2022-01-01T00:00:00Z2022 Mar2026-05-31T11:47:43.022Z2024-11-10T07:25:49.883ZS-EPMC89203303511381510.1172/JCI152780