Interleukin-1α deficiency attenuates endoplasmic reticulum stress-induced liver damage and CHOP expression in mice

Kandel-Kfir, Michal; Almog, Tal; Shaish, Aviv; Shlomai, Gadi; Anafi, Liat; Avivi, Camila; Barshack, Iris; Grosskopf, Itamar; Harats, Dror; Kamari, Yehuda

doi:10.1016/j.jhep.2015.05.012

Cited by 36 publications

(25 citation statements)

References 57 publications

(94 reference statements)

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“…(12,13) In turn, deletion of key inflammatory mediators reduces ER stress and protects against liver disease progression. (14,15) Recent studies also demonstrated that ER stress inhibits the functional shift from proinflammatory to restorative activation of macrophages. (16)(17)(18) However, the interactions between HCs and macrophages during ER stress in both cell types' response remain unclear.…”

Section: Vitamin D Receptor Activation In Liver Macrophages Protects mentioning

confidence: 99%

“…ER stress–associated liver injuries are frequently characterized by infiltration and proinflammatory activation of macrophages, whereas alleviation of ER stress can attenuate inflammation . In turn, deletion of key inflammatory mediators reduces ER stress and protects against liver disease progression . Recent studies also demonstrated that ER stress inhibits the functional shift from proinflammatory to restorative activation of macrophages .…”

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confidence: 99%

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Vitamin D Receptor Activation in Liver Macrophages Protects Against Hepatic Endoplasmic Reticulum Stress in Mice

et al. 2020

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Background and Aims Hepatic endoplasmic reticulum (ER) stress, whether triggered by intrinsic or extrinsic factors, can be resolved by the unfolded protein response (UPR). Sustained UPR activation leads to cell death and inflammatory response and contributes to liver disease progression. Hepatic tissue macrophages are key players in orchestrating liver inflammation, and ER stress can enhance macrophage activation. However, it is not well defined how the interplay between ER stress and inflammation is regulated during hepatic stress response. Approach and Results Here we demonstrate that vitamin D receptor (VDR) activation mitigates hepatic ER stress response, whereas VDR knockout mice undergo persistent UPR activation and apoptosis in response to chemical ER stress inducer. Moreover, VDR deficiency promotes hepatic macrophage infiltration and increases gene expression and systematic levels of proinflammatory cytokines, including interleukin (IL)‐1β, IL‐6, and tumor necrosis factor α. VDR expression is induced in hepatic macrophages by ER stress, and VDR plays a dual regulatory role in macrophages by protecting against ER stress and promoting anti‐inflammatory polarization. Co‐culture with VDR‐activated bone marrow–derived macrophages suppresses UPR target genes in primary hepatocytes treated with ER stress inducers. Thus, the immunomodulatory functions of VDR in macrophages are critical in hepatic ER stress resolution in mice. Conclusions VDR signaling in macrophages regulates a shift between proinflammatory and anti‐inflammatory activation during ER stress–induced inflammation to promote hepatic ER stress resolution.

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Section: Vitamin D Receptor Activation In Liver Macrophages Protects mentioning

confidence: 99%

mentioning

confidence: 99%

Vitamin D Receptor Activation in Liver Macrophages Protects Against Hepatic Endoplasmic Reticulum Stress in Mice

et al. 2020

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“…On the other hand, reduced inflammation ameliorates ER stress-induced liver injury. Kandel-Kfir et al showed that IL-1 α deficient mice display reduced inflammation, hepatocyte death, and liver damage in an ER stress-induced steatohepatitis model [48]. These studies help to understand a complex puzzle of NASH pathogenesis, aiding in the elucidation of ER stress risk factors involved in NASH development.…”

Section: Lipotoxic Hepatocyte Injuries Oxidative Stress and Er Smentioning

confidence: 99%

Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells

Magee

Zou

Zhang

2016

BioMed Research International

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Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in the Western countries, affecting up to 25% of the general population and becoming a major health concern in both adults and children. NAFLD encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is a manifestation of the metabolic syndrome and hepatic disorders with the presence of steatosis, hepatocyte injury (ballooning), inflammation, and, in some patients, progressive fibrosis leading to cirrhosis. The pathogenesis of NASH is a complex process and implicates cell interactions between liver parenchymal and nonparenchymal cells as well as crosstalk between various immune cell populations in liver. Lipotoxicity appears to be the central driver of hepatic cellular injury via oxidative stress and endoplasmic reticulum (ER) stress. This review focuses on the contributions of hepatocytes and nonparenchymal cells to NASH, assessing their potential applications to the development of novel therapeutic agents. Currently, there are limited pharmacological treatments for NASH; therefore, an increased understanding of NASH pathogenesis is pertinent to improve disease interventions in the future.

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“…To our knowledge, a variety of cytokines, including those expressed or secreted by hepatocytes, evoke inflammatory responses and promote cell death in liver diseases. In a diet-induced steatohepatitis mouse model, hepatocyte IL-1α was found to be upregulated in response to ER stress, which in turn enhanced CHOP expression; IL-1α released from necrotic hepatocytes accelerates steatohepatitis via induction of inflammatory cytokines [33, 34]. In lipopolysaccharide (LPS)-induced liver injury, hepatocyte-derived IL-7 augmented CD8+ T cell cytotoxic activity and promoted the development of autoimmune diseases [35].…”

Section: Discussionmentioning

confidence: 99%

Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver

Wang

Zhao

et al. 2019

Preprint

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Endoplasmic reticulum (ER) stress-associated cell death is prevalent in various liver diseases. However, the determinant mechanism how hepatocytes survive unresolved stress was still unclear. Interleukin-24 (IL-24) was previously found to promote ER stress-mediated cell death, and yet its expression and function in the liver remained elusive. Here we identified an anti-apoptotic role of IL-24, which transiently accumulated within ER-stressed hepatocytes in a X-box binding protein 1 (XBP1)-dependent manner. Disruption of IL-24 increased cell death in the CCL4- or APAP-challenged mouse liver or Tm-treated hepatocytes. In contrast, pharmaceutical blockade of eukaryotic initiation factor 2α (eIF2α) or genetical ablation of C/EBP homologous protein (CHOP) restored hepatocyte function in the absence of IL-24. In a clinical setting, patients with acute liver failure manifested a profound decrease of hepatic IL-24 expression, which was associated with disease progression. In conclusion, intrinsic hepatocyte IL-24 maintains ER homeostasis by restricting the eIF2α-CHOP pathway-mediated stress signal, which might be exploited as a bio-index for prognosis or therapeutic intervention in patients with liver injury.

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Interleukin-1α deficiency attenuates endoplasmic reticulum stress-induced liver damage and CHOP expression in mice

Cited by 36 publications

References 57 publications

Vitamin D Receptor Activation in Liver Macrophages Protects Against Hepatic Endoplasmic Reticulum Stress in Mice

Vitamin D Receptor Activation in Liver Macrophages Protects Against Hepatic Endoplasmic Reticulum Stress in Mice

Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells

Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver

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