TY - JOUR
T1 - Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells
AU - Morikawa, Shuntaro
AU - Blacher, Lindsey
AU - Onwumere, Chinyere
AU - Urano, Fumihiko
N1 - Funding Information:
FU thanks philanthropic supports from the Silberman Fund, the Ellie White Foundation for the Rare Genetic Disorders, the Snow Foundation, the Unravel Wolfram Syndrome Fund, the Stowe Fund, the Eye Hope Foundation, the Feiock Fund, the Cachia Fund, the Gildenhorn Fund, Ontario Wolfram League, Associazione Gentian—Sindrome di Wolfram Italia, Alianza de Familias Afectadas por el Sindrome Wolfram Spain, Wolfram syndrome UK, and Association Syndrome de Wolfram France. FU also thanks all the members of the Washington University Wolfram Syndrome Study, Research Clinic, and WFS1 Clinic at the Washington University Medical Center for their support ( https://wolframsyndrome.wustl.edu ) and all the participants in the Wolfram syndrome International Registry and Clinical Study, Research Clinic, and Clinical Trials for their time and efforts. SM acknowledges Diane Bender and Kohei Omachi (both in Washington University in St. Louis) for their skilled technical supports and Kohsuke Kanekura (Tokyo Medical University) for his critical review of the manuscript. The authors are grateful to Cris Brown (Washington University in St. Louis) for her general support. This work was supported, in part, by the Bursky Center for Human Immunology and Immunotherapy Programs at Washington University in St. Louis, Immunomonitoring Laboratory. We are grateful for the critical review and editing assistance provided by InPrint: A Scientific Communication Network at Washington University in St. Louis.
Funding Information:
FU thanks philanthropic supports from the Silberman Fund, the Ellie White Foundation for the Rare Genetic Disorders, the Snow Foundation, the Unravel Wolfram Syndrome Fund, the Stowe Fund, the Eye Hope Foundation, the Feiock Fund, the Cachia Fund, the Gildenhorn Fund, Ontario Wolfram League, Associazione Gentian?Sindrome di Wolfram Italia, Alianza de Familias Afectadas por el Sindrome Wolfram Spain, Wolfram syndrome UK, and Association Syndrome de Wolfram France. FU also thanks all the members of the Washington University Wolfram Syndrome Study, Research Clinic, and WFS1 Clinic at the Washington University Medical Center for their support (https://wolframsyndrome.wustl.edu) and all the participants in the Wolfram syndrome International Registry and Clinical Study, Research Clinic, and Clinical Trials for their time and efforts. SM acknowledges Diane Bender and Kohei Omachi (both in Washington University in St. Louis) for their skilled technical supports and Kohsuke Kanekura (Tokyo Medical University) for his critical review of the manuscript. The authors are grateful to Cris Brown (Washington University in St. Louis) for her general support. This work was supported, in part, by the Bursky Center for Human Immunology and Immunotherapy Programs at Washington University in St. Louis, Immunomonitoring Laboratory. We are grateful for the critical review and editing assistance provided by InPrint: A Scientific Communication Network at Washington University in St. Louis.
Funding Information:
This work was partly supported by the grants from the National Institutes of Health (NIH)/NIDDK (DK112921, DK020579). SM was supported by Manpei Suzuki Diabetes Foundation and Japan Society for the Promotion of Science (JSPS) Overseas Research Fellowships.
Publisher Copyright:
Copyright © 2022 Morikawa, Blacher, Onwumere and Urano.
PY - 2022/3/25
Y1 - 2022/3/25
N2 - 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.
AB - 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.
KW - Wolfram syndrome
KW - diabetes
KW - endoplasmic reticulum stress
KW - inflammation
KW - macrophage
KW - unfolded protein response
UR - http://www.scopus.com/inward/record.url?scp=85128413485&partnerID=8YFLogxK
U2 - 10.3389/fendo.2022.849204
DO - 10.3389/fendo.2022.849204
M3 - Article
C2 - 35399956
AN - SCOPUS:85128413485
SN - 1664-2392
VL - 13
JO - Frontiers in Endocrinology
JF - Frontiers in Endocrinology
M1 - 849204
ER -