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: Adi Gilboa-Geffen, Yochai Wolf, Geula Hanin, Naomi Melamed-Book, Marjorie Pick, Estelle R Bennett, David S Greenberg, Susan Lester, Maureen Rischmueller, Hermona Soreq
• Journal: PloS one (PLoS One) Vol. 6 Issue 12 Pg. e28727 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 22174879 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Inflammation Mediators
• NF-kappa B
• Toll-Like Receptor 9

Topics

• Animals
• Biomarkers (metabolism)
• Cell Line
• Disease Models, Animal
• Humans
• Inflammation Mediators (metabolism)
• Leukocytes, Mononuclear (pathology)
• Mice
• NF-kappa B (metabolism)
• Saliva (metabolism)
• Salivary Glands (metabolism, pathology, physiopathology)
• Signal Transduction
• Sjogren's Syndrome (metabolism, pathology, physiopathology)
• Toll-Like Receptor 9 (agonists, deficiency)