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Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells

Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and progressive neurodegeneration. Pathogenic variants in the WFS1 gene are the main causes of Wolfram syndrome. WFS1 encodes a transmembrane protein...

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Autores principales: Morikawa, Shuntaro, Blacher, Lindsey, Onwumere, Chinyere, Urano, Fumihiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990750/
https://www.ncbi.nlm.nih.gov/pubmed/35399956
http://dx.doi.org/10.3389/fendo.2022.849204
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author Morikawa, Shuntaro
Blacher, Lindsey
Onwumere, Chinyere
Urano, Fumihiko
author_facet Morikawa, Shuntaro
Blacher, Lindsey
Onwumere, Chinyere
Urano, Fumihiko
author_sort Morikawa, Shuntaro
collection PubMed
description Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and progressive neurodegeneration. Pathogenic variants in the WFS1 gene are the main causes of Wolfram syndrome. WFS1 encodes a transmembrane protein localized to the endoplasmic reticulum (ER) and regulates the unfolded protein response (UPR). Loss of function of WFS1 leads to dysregulation of insulin production and secretion, ER calcium depletion, and cytosolic calpains activation, resulting in activation of apoptotic cascades. Although the terminal UPR has been shown to induce inflammation that accelerates pancreatic β-cell dysfunction and death in diabetes, the contribution of pancreatic β-cell inflammation to the development of diabetes in Wolfram syndrome has not been fully understood. Here we show that WFS1-deficiency enhances the gene expression of pro-inflammatory cytokines and chemokines, leading to cytokine-induced ER-stress and cell death in pancreatic β-cells. PERK and IRE1α pathways mediate high glucose-induced inflammation in a β-cell model of Wolfram syndrome. M1-macrophage infiltration and hypervascularization are seen in the pancreatic islets of Wfs1 whole-body knockout mice, demonstrating that WFS1 regulates anti-inflammatory responses in pancreatic β-cells. Our results indicate that inflammation plays an essential role in the progression of β-cell death and diabetes in Wolfram syndrome. The pathways involved in ER stress-mediated inflammation provide potential therapeutic targets for the treatment of Wolfram syndrome.
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spelling pubmed-89907502022-04-09 Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells Morikawa, Shuntaro Blacher, Lindsey Onwumere, Chinyere Urano, Fumihiko Front Endocrinol (Lausanne) Endocrinology Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and progressive neurodegeneration. Pathogenic variants in the WFS1 gene are the main causes of Wolfram syndrome. WFS1 encodes a transmembrane protein localized to the endoplasmic reticulum (ER) and regulates the unfolded protein response (UPR). Loss of function of WFS1 leads to dysregulation of insulin production and secretion, ER calcium depletion, and cytosolic calpains activation, resulting in activation of apoptotic cascades. Although the terminal UPR has been shown to induce inflammation that accelerates pancreatic β-cell dysfunction and death in diabetes, the contribution of pancreatic β-cell inflammation to the development of diabetes in Wolfram syndrome has not been fully understood. Here we show that WFS1-deficiency enhances the gene expression of pro-inflammatory cytokines and chemokines, leading to cytokine-induced ER-stress and cell death in pancreatic β-cells. PERK and IRE1α pathways mediate high glucose-induced inflammation in a β-cell model of Wolfram syndrome. M1-macrophage infiltration and hypervascularization are seen in the pancreatic islets of Wfs1 whole-body knockout mice, demonstrating that WFS1 regulates anti-inflammatory responses in pancreatic β-cells. Our results indicate that inflammation plays an essential role in the progression of β-cell death and diabetes in Wolfram syndrome. The pathways involved in ER stress-mediated inflammation provide potential therapeutic targets for the treatment of Wolfram syndrome. Frontiers Media S.A. 2022-03-25 /pmc/articles/PMC8990750/ /pubmed/35399956 http://dx.doi.org/10.3389/fendo.2022.849204 Text en Copyright © 2022 Morikawa, Blacher, Onwumere and Urano https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Morikawa, Shuntaro
Blacher, Lindsey
Onwumere, Chinyere
Urano, Fumihiko
Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells
title Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells
title_full Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells
title_fullStr Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells
title_full_unstemmed Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells
title_short Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells
title_sort loss of function of wfs1 causes er stress-mediated inflammation in pancreatic beta-cells
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990750/
https://www.ncbi.nlm.nih.gov/pubmed/35399956
http://dx.doi.org/10.3389/fendo.2022.849204
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