Metformin-induced activation of Ca2+ signaling prevents immune infiltration/pathology in Sjogren’s syndrome-prone mouse models

IF 4.7 Q2 IMMUNOLOGY
Viviane Nascimento Da Conceicao , Yuyang Sun , Xiufang Chai , Julian L. Ambrus , Bibhuti B. Mishra , Brij B. Singh
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引用次数: 0

Abstract

Immune cell infiltration and glandular dysfunction are the hallmarks of autoimmune diseases such as primary Sjogren’s syndrome (pSS), however, the mechanism(s) is unknown. Our data show that metformin-treatment induces Ca2+ signaling that restores saliva secretion and prevents immune cell infiltration in the salivary glands of IL14α-transgenic mice (IL14α), which is a model for pSS. Mechanistically, we show that loss of Ca2+ signaling is a major contributing factor, which is restored by metformin treatment, in IL14α mice. Furthermore, the loss of Ca2+ signaling leads to ER stress in salivary glands. Finally, restoration of metformin-induced Ca2+ signaling inhibited the release of alarmins and prevented the activation of ER stress that was essential for immune cell infiltration. These results suggest that loss of metformin-mediated activation of Ca2+ signaling prevents ER stress, which inhibited the release of alarmins that induces immune cell infiltration leading to salivary gland dysfunction observed in pSS.

二甲双胍诱导的Ca2+信号激活可防止干燥综合征易发小鼠模型的免疫浸润/病理
免疫细胞浸润和腺体功能障碍是原发性干燥综合征(pSS)等自身免疫性疾病的标志,但其机制尚不清楚。我们的数据表明,二甲双胍处理诱导Ca2+信号,恢复唾液分泌,阻止免疫细胞浸润IL14α-转基因小鼠(IL14α)的唾液腺,这是pSS的模型。在机制上,我们发现Ca2+信号的丢失是一个主要的促成因素,在IL14α小鼠中通过二甲双胍治疗恢复。此外,Ca2+信号的丢失导致唾液腺内质网应激。最后,二甲双胍诱导的Ca2+信号的恢复抑制了警报的释放,并阻止了免疫细胞浸润所必需的内质网应激的激活。这些结果表明,二甲双胍介导的Ca2+信号激活的丧失可以阻止内质网应激,从而抑制诱发免疫细胞浸润的警报器的释放,从而导致pSS中观察到的唾液腺功能障碍。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Translational Autoimmunity
Journal of Translational Autoimmunity Medicine-Immunology and Allergy
CiteScore
7.80
自引率
2.60%
发文量
33
审稿时长
55 days
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