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Metformin-induced activation of Ca(2+) signaling prevents immune infiltration/pathology in Sjogren’s syndrome-prone mouse models

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 infiltrati...

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Autores principales: Nascimento Da Conceicao, Viviane, Sun, Yuyang, Chai, Xiufang, Ambrus, Julian L., Mishra, Bibhuti B., Singh, Brij B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10497794/
https://www.ncbi.nlm.nih.gov/pubmed/37711153
http://dx.doi.org/10.1016/j.jtauto.2023.100210
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author Nascimento Da Conceicao, Viviane
Sun, Yuyang
Chai, Xiufang
Ambrus, Julian L.
Mishra, Bibhuti B.
Singh, Brij B.
author_facet Nascimento Da Conceicao, Viviane
Sun, Yuyang
Chai, Xiufang
Ambrus, Julian L.
Mishra, Bibhuti B.
Singh, Brij B.
author_sort Nascimento Da Conceicao, Viviane
collection PubMed
description 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.
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spelling pubmed-104977942023-09-14 Metformin-induced activation of Ca(2+) signaling prevents immune infiltration/pathology in Sjogren’s syndrome-prone mouse models Nascimento Da Conceicao, Viviane Sun, Yuyang Chai, Xiufang Ambrus, Julian L. Mishra, Bibhuti B. Singh, Brij B. J Transl Autoimmun Research paper 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. Elsevier 2023-09-09 /pmc/articles/PMC10497794/ /pubmed/37711153 http://dx.doi.org/10.1016/j.jtauto.2023.100210 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research paper
Nascimento Da Conceicao, Viviane
Sun, Yuyang
Chai, Xiufang
Ambrus, Julian L.
Mishra, Bibhuti B.
Singh, Brij B.
Metformin-induced activation of Ca(2+) signaling prevents immune infiltration/pathology in Sjogren’s syndrome-prone mouse models
title Metformin-induced activation of Ca(2+) signaling prevents immune infiltration/pathology in Sjogren’s syndrome-prone mouse models
title_full Metformin-induced activation of Ca(2+) signaling prevents immune infiltration/pathology in Sjogren’s syndrome-prone mouse models
title_fullStr Metformin-induced activation of Ca(2+) signaling prevents immune infiltration/pathology in Sjogren’s syndrome-prone mouse models
title_full_unstemmed Metformin-induced activation of Ca(2+) signaling prevents immune infiltration/pathology in Sjogren’s syndrome-prone mouse models
title_short Metformin-induced activation of Ca(2+) signaling prevents immune infiltration/pathology in Sjogren’s syndrome-prone mouse models
title_sort metformin-induced activation of ca(2+) signaling prevents immune infiltration/pathology in sjogren’s syndrome-prone mouse models
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10497794/
https://www.ncbi.nlm.nih.gov/pubmed/37711153
http://dx.doi.org/10.1016/j.jtauto.2023.100210
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