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Compound A attenuates proinflammatory cytokine-induced endoplasmic reticulum stress in beta cells and displays beneficial therapeutic effects in a mouse model of autoimmune diabetes

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Abstract

Type 1 diabetes (T1D) is characterized by an immune-mediated progressive destruction of the insulin-producing β-cells. Proinflammatory cytokines trigger endoplasmic reticulum (ER) stress and subsequent insulin secretory deficiency in cultured β-cells, mimicking the islet microenvironment in T1D. β-cells undergo physiologic ER stress due to the high rate of insulin production and secretion under stimulated conditions. Severe and uncompensated ER stress in β-cells is induced by several pathological mechanisms before onset and during T1D. We previously described that the small drug Compound A (CpdA), a selective glucocorticoid receptor (GR/NR3C1, nuclear receptor subfamily 3, group C, member 1) ligand with demonstrated inflammation-suppressive activity in vivo, is an effective modulator of effector T and dendritic cells and of macrophages, yet, in a GR-independent manner. Here, we focus on CpdA’s therapeutic potential in T1D cellular and animal models. We demonstrate that CpdA improves the unfolded protein response (UPR) by attenuating ER stress and favoring the survival and function of β-cells exposed to an environment of proinflammatory cytokines. CpdA administration to NODscid mice adoptively transferred with diabetogenic splenocytes (from diabetic NOD mice) led to a delay of disease onset and reduction of diabetes incidence. Histological analysis of the pancreas showed a reduction in islet leukocyte infiltration (insulitis) and preservation of insulin expression in CpdA-treated normoglycemic mice in comparison with control group. These new findings together with our previous reports justify further studies on the administration of this small molecule as a novel therapeutic strategy with dual targets (effector immune and β-cells) during autoimmune diabetes.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

CpdA:

Compound A

eIF2α:

Eukaryotic translation initiation factor 2α

ER:

Endoplasmic reticulum

GR:

Glucocorticoid receptor

GSIS:

Glucose-stimulated insulin secretion

SEGRAM:

Selective glucocorticoid receptor agonists and modulators

STZ:

Streptozotocin

T1D:

Type 1 diabetes

UPR:

Unfolded protein response

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Acknowledgements

The 5xATF6-LUC and XBP1u-LUC plasmids were a kind gift from Prof. Dr. Sarah Gerlo (Univ. Ghent, Belgium).

Funding

This work was supported by grants from Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT #2018–1577 to MJP and #2018–719 to LA); from Universidad Austral (#2020 to MJP and LA); and from Sociedad Argentina de Diabetes (#2018 to MJP and #2019 to LA). Also, we thank the support of Fundación Marjorie para la Investigación en Diabetes (www.fumdiab.org.ar).

Author information

Authors and Affiliations

  1. Laboratory of Immuno-Endocrinology, Diabetes and Metabolism, Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET–Universidad Austral, Av. Pte. Perón 1500 (B1629AHJ), Pilar, Buenos Aires, Argentina

    Luz Andreone, Florencia Fuertes, Carolina Sétula, Andres E. Barcala Tabarrozzi, Miranda S. Orellano & Marcelo J. Perone

  2. Laboratorio de Terapia Génica Y Células Madre, Instituto Tecnológico de Chascomús (INTECH), CONICET-UNSAM, Buenos Aires, Argentina

    Ricardo A. Dewey

  3. Imagine Pharma, Pittsburgh, Pennsylvania, PA and Allegheny Health Network, Pittsburgh, PA, USA

    Rita Bottino

  4. Receptor Research Laboratories, Nuclear Receptor Lab, VIB-Department of Medical Protein Research, VIB, Ghent University, Ghent, Belgium

    Karolien De Bosscher

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  1. Luz Andreone
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Contributions

LA and MJP conceived and designed the work. LA, FF and CS performed the in vitro experiments and acquired data. LA, MJP and AEBT performed the animal experiments and acquired data. RB provided de human islets. MSO contributed to sample preparation and data acquisition. LA and MJP interpreted the data and wrote the manuscript. RAD made important contributions in the interpretation of the results. KDB provided CpdA and research tools supported by FWO-Vlaanderen (G044217N) and contributed to the interpretation of data. All authors gave final approval of the version to be published. MJP is the guarantor of this work, has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding author

Correspondence to Marcelo J. Perone.

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All experimental procedures were conducted in accordance with the Guide for the care and use of laboratory animals, Eighth edition (2011) and were approved by the Animal Research and Care Committee (#0001 & #0069), FCEyN, University of Buenos Aires.

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Andreone, L., Fuertes, F., Sétula, C. et al. Compound A attenuates proinflammatory cytokine-induced endoplasmic reticulum stress in beta cells and displays beneficial therapeutic effects in a mouse model of autoimmune diabetes. Cell. Mol. Life Sci. 79, 587 (2022). https://doi.org/10.1007/s00018-022-04615-5

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