activation of the alternative nfκb pathway improves disease symptoms in a model of sjogrens syndrome激活的替代nfκb途径改善疾病症状干燥综合征的典范.pdfVIP

Activation of the Alternative NFkB Pathway Improves Disease Symptoms in a Model of Sjogren’s Syndrome 1 1 1 1 1 Adi Gilboa-Geffen , Yochai Wolf , Geula Hanin , Naomi Melamed-Book , Marjorie Pick , Estelle R. 1 1 2 2 1,3 Bennett , David S. Greenberg , Susan Lester , Maureen Rischmueller , Hermona Soreq * 1 Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel, 2 Rheumatology Unit, Queen Elizabeth Hospital, Woodville, Australia, 3 The Edmond and Lily Safra Center of Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel 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 TLR92/ 2 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-kB 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-kB 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 TLR92/ 2 mice were resistant