Activation of the alternative NFκB pathway improves disease symptoms in a model of Sjogren's syndrome

• Published in: PloS one 2011-12, Vol.6 (12), p.e28727-e28727
• Main Authors: Gilboa-Geffen, Adi, Wolf, Yochai, Hanin, Geula, Melamed-Book, Naomi, Pick, Marjorie, Bennett, Estelle R, Greenberg, David S, Lester, Susan, Rischmueller, Maureen, Soreq, Hermona
• Format: Article
• Language: English
• Subjects: Activation; Animals; Aptamers; Biology; Biomarkers; Biomarkers - metabolism; Cell Line; Deoxyribonucleic acid; Diabetes mellitus; Disease Models, Animal; DNA; Glands; Humans; Immune system; Immunoglobulins; Inflammation Mediators - metabolism; Inflammatory response; Inhibitors; Kinases; Leukocytes, Mononuclear - pathology; Lymphocytes; Medicine; Mice; Mortality; NF-kappa B - metabolism; NF-κB protein; Oligonucleotides; Parkinson's disease; Patients; Proteins; Rheumatology; Rodents; Saliva - secretion; Salivary gland; Salivary glands; Salivary Glands - metabolism; Salivary Glands - pathology; Salivary Glands - physiopathology; Signal Transduction; Signaling; Sjogren's syndrome; Sjogren's Syndrome - metabolism; Sjogren's Syndrome - pathology; Sjogren's Syndrome - physiopathology; TLR9 protein; Toll-Like Receptor 9 - agonists; Toll-Like Receptor 9 - deficiency; Toll-like receptors; Trends
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0028727

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.