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

Viviane Nascimento Da Conceicao; Yuyang Sun; Xiufang Chai; Julian L Ambrus; Bibhuti B Mishra; Brij B Singh

doi:10.1016/j.jtauto.2023.100210

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

J Transl Autoimmun. 2023 Sep 9:7:100210. doi: 10.1016/j.jtauto.2023.100210. eCollection 2023 Dec.

Authors

Viviane Nascimento Da Conceicao¹, Yuyang Sun¹, Xiufang Chai¹, Julian L Ambrus², Bibhuti B Mishra³, Brij B Singh¹

Affiliations

¹ Department of Periodontics, School of Dentistry, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.
² Division of Allergy, Immunology, and Rheumatology, Department of Medicine, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14203, USA.
³ Department of Developmental Dentistry, School of Dentistry, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.

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.

Keywords: Alarmins; Ca2+ signaling; ER stress; Metformin, immune cell activation; Primary Sjogren’s syndrome; Salivary gland dysfunction.