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Endoplasmic Reticulum Stress in Macrophages: The Vicious Circle of Lipid Accumulation and Pro-Inflammatory Response.

ABSTRACT: The endoplasmic reticulum (ER) stress is an important event in the pathogenesis of different human disorders, including atherosclerosis. ER stress leads to disturbance of cellular homeostasis, apoptosis, and in the case of macrophages, to foam cell formation and pro-inflammatory cytokines production. In atherosclerosis, several cell types can be affected by ER stress, including endothelial cells, vascular smooth muscular cells, and macrophages. Modified low-density lipoproteins (LDL) and cytokines, in turn, can provoke ER stress through different processes. The signaling cascades involved in ER stress initiation are complex and linked to other cellular processes, such as lysosomal biogenesis and functioning, autophagy, mitochondrial homeostasis, and energy production. In this review, we discuss the underlying mechanisms of ER stress formation and the interplay of lipid accumulation and pro-inflammatory response. We will specifically focus on macrophages, which are the key players in maintaining chronic inflammatory milieu in atherosclerotic lesions, and also a major source of lipid-accumulating foam cells.

SUBMITTER: Sukhorukov VN

PROVIDER: S-EPMC7400097 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Endoplasmic Reticulum Stress in Macrophages: The Vicious Circle of Lipid Accumulation and Pro-Inflammatory Response.

Sukhorukov Vasily N VN Khotina Victoria A VA Bagheri Ekta Mariam M Ivanova Ekaterina A EA Sobenin Igor A IA Orekhov Alexander N AN

Biomedicines 20200713 7

The endoplasmic reticulum (ER) stress is an important event in the pathogenesis of different human disorders, including atherosclerosis. ER stress leads to disturbance of cellular homeostasis, apoptosis, and in the case of macrophages, to foam cell formation and pro-inflammatory cytokines production. In atherosclerosis, several cell types can be affected by ER stress, including endothelial cells, vascular smooth muscular cells, and macrophages. Modified low-density lipoproteins (LDL) and cytokin ...[more]

PMID: 32668733

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Project description:BackgroundAdult human pancreatic beta cells are the "gold standard" for studies on diabetes pathogenesis, but their use is limited by insufficient availability and variable quality. An important effort has recently taken place to differentiate beta cells from human induced pluripotent stem cells (iPSCs) and validate their use for diabetes research. We presently used a 7-stage protocol to generate beta cells from human iPSC and evaluated whether these cells are responsive to the pro-inflammatory cytokines (IFN?, IL-1?, or IFN?) that play a role in type 1 diabetes.MethodsThe iPSC-derived islet-like cell clusters contained 40-50% beta and 10-15% alpha cells and expressed the receptors for IFN?, IL-1?, or IFN?. Cells were exposed to either IFN? (1000?U/mL)?+?IL-1? (50?U/mL) or IFN? alone (2000?U/mL) for 24/48?h. Apoptosis was quantified using Hoechst/propidium iodide staining or the RealTime Glo Apoptosis Kit (Promega). After treatment, CXCL10 secretion was quantified by ELISA. The expression of multiples genes (Ins, Gcg, Nkx2.2, Nkx6.1, Pdx1, Mafa, BiP, Chop, Atf3, CXCL10, CXCL9, CCL5, and HLA-ABC) was quantified by RT-qPCR. Phosphorylation state and total expression of STAT1/STAT2, as well as expression of PDL1 and of the ER chaperone BiP, were quantified by Western blotting. The co-localization of HLA-ABC or cleaved caspase-3 and Ins/Gcg expression was assessed by immunohistochemistry. The presence of HLA-ABC at the plasma membrane was measured by flow cytometry.ResultsIFN? + IL-1? and IFN? induced apoptosis of the cells after 48?h of exposure. Cleaved caspase-3 co-localized mostly but not exclusively with Ins+ cells. Exposure to IFN? + IL-1? induced a pro-inflammatory phenotype, including increased CXCL10, CXCL9, and CCL5 expression; CXCL10 secretion; and HLA-ABC expression. HLA overexpression was confirmed at the protein level by Western blotting and flow cytometry. Exposure to IFN? + IL-1? (but not IFN?) also induced beta cell dedifferentiation and endoplasmic reticulum stress (increase in BiP, Chop, and Atf3 mRNA expression). Phosphorylation of STAT1 was stimulated already after 1?h by IFN? + IL-1? and IFN?, while phosphorylation of STAT2 was only activated by IFN? at 1-4 h. PDL1 expression was increased by both IFN? + IL-1? and IFN?.ConclusionsOur data show that human iPSC-derived beta cells respond to pro-inflammatory cytokines IL-1? + IFN? and IFN?, by activating the same pathogenic processes as adult human primary beta cells. These cells thus represent a valuable tool for future research on the pathogenesis of type 1 diabetes.

Dataset Information

Endoplasmic Reticulum Stress in Macrophages: The Vicious Circle of Lipid Accumulation and Pro-Inflammatory Response.

Publications

Endoplasmic Reticulum Stress in Macrophages: The Vicious Circle of Lipid Accumulation and Pro-Inflammatory Response.

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