title: Activation of the alternative NFκB pathway improves disease symptoms in a model of Sjogren's syndrome.
abstract: The purpose of our study was to understand if Toll-like receptor 9 (TLR9) activation could contribute to the control of inflammation in Sjogren's syndrome. To this end, we manipulated TLR9 signaling in non-obese diabetic (NOD) and TLR9(-/-) mice using agonistic CpG oligonucleotide aptamers, TLR9 inhibitors, and the in-house oligonucleotide BL-7040. We then measured salivation, inflammatory response markers, and expression of proteins downstream to NF-κB activation pathways. Finally, we labeled proteins of interest in salivary gland biopsies from Sjogren's syndrome patients, compared to Sicca syndrome controls. We show that in NOD mice BL-7040 activates TLR9 to induce an alternative NF-κB activation mode resulting in increased salivation, elevated anti-inflammatory response in salivary glands, and reduced peripheral AChE activity. These effects were more prominent and also suppressible by TLR9 inhibitors in NOD mice, but TLR9(-/-) mice were resistant to the salivation-promoting effects of CpG oligonucleotides and BL-7040. Last, salivary glands from Sjogren's disease patients showed increased inflammatory and decreased anti-inflammatory biomarkers, in addition to decreased levels of alternative NF-κB pathway proteins. In summary, we have demonstrated that activation of TLR9 by BL-7040 leads to non-canonical activation of NF-κB, promoting salivary functioning and down-regulating inflammation. We propose that BL-7040 could be beneficial in treating Sjogren's syndrome and may be applicable to additional autoimmune syndromes.
authors.affiliation: Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Gilboa-Geffen
authors.forename: Yochai
authors.initials: Y
authors.lastname: Wolf
authors.forename: Geula
authors.initials: G
authors.lastname: Hanin
authors.forename: Naomi
authors.initials: N
authors.lastname: Melamed-Book
authors.forename: Marjorie
authors.initials: M
authors.lastname: Pick
authors.forename: Estelle R
authors.initials: ER
authors.lastname: Bennett
authors.forename: David S
authors.initials: DS
authors.lastname: Greenberg
authors.forename: Susan
authors.initials: S
authors.lastname: Lester
authors.forename: Maureen
authors.initials: M
authors.lastname: Rischmueller
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D012463:Saliva / Q000378:metabolism; D012469:Salivary Glands / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000172:deficiency
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D016328:NF-kappa B; D051217:Toll-Like Receptor 9