Artesunate inhibits Sjögren's syndrome-like autoimmune responses and BAFF-induced B cell hyperactivation via TRAF6-mediated NF-κB signaling.
BACKGROUND
Hyperactivation of B cells by activators has been demonstrated to play a central role in the pathogenesis of Sjögren's syndrome (SS). In this study, we found that artesunate (ART) can attenuate BAFF-induced B cell hyperactivation and SS-like symptoms in NOD/Ltj mice.


PURPOSE
To determine the efficacy of ART in attenuating SS-like symptoms in vivo and explore the underlying mechanism in vitro.


STUDY DESIGN
ART was intragastrically injected into SS-like NOD/Ltj mice. The cytokine hsBAFF was used to activate Raji and Daudi B cells to mimic B cell hyperactivation in vitro.


METHODS
The efficacy of ART in inhibiting SS progression was studied in NOD/Ltj mice. Salivary flow rate, the number of lymphocytic infiltration foci, the level of autoantibodies and the extent of B cell infiltration were measured in the indicated groups. CCK-8 assays, flow cytometry-based EdU staining and Annexin V/PI staining were also used to detect the effect of ART on the survival and proliferation mechanism in BAFF-induced Raji and Daudi cells. Further studies determined that TRAF6 degradation is a potential mechanism by which ART determines B cell fate.


RESULTS
Treatment with ART inhibited lymphocytic foci formation, B cell infiltration and autoantibody secretion in SS-like NOD/Ltj mice. In vitro assay results indicated that ART effectively inhibited BAFF-induced viability, survival and proliferation of neoplastic B cells. Mechanistically, ART targeted BAFF-activated NFκB by regulating the proteasome-mediated degradation of TRAF6 in Raji and Daudi cells.


CONCLUSION
ART ameliorated murine SS-like symptoms and regulated TRAF6-NFκB signaling, thus determining survival and proliferation of B cells.
['Zhan|Tianle|T|', 'Wang|Baoli|B|', 'Fu|Jiayao|J|', 'Shao|Yanxiong|Y|', 'Ye|Lei|L|', 'Shi|Huan|H|', 'Zheng|Lingyan|L|']
D000818:Animals D000077332:Artesunate D001323:Autoantibodies D015551:Autoimmunity D053264:B-Cell Activating Factor D001402:B-Lymphocytes D045744:Cell Line, Tumor D004195:Disease Models, Animal D006801:Humans D007155:Immunologic Factors D047908:Intracellular Signaling Peptides and Proteins D008214:Lymphocytes D008813:Mice, Inbred ICR D016688:Mice, Inbred NOD D016328:NF-kappa B D012469:Salivary Glands D015398:Signal Transduction D012859:Sjogren's Syndrome
Artesunate Sjögren's syndrome TRAF6 NFκB BAFF Ubiquitination