Inactivation of C/ebp Homologous Protein-driven Immune-Metabolic Interactions Exacerbate Obesity and Adipose Tissue Leukocytosis

Grant, Ryan W.; Nguyen, Kim Thuy; Ravussin, Anthony; Albarado, Diana C.; Youm, Yun‐Hee; Dixit, Vishwa Deep

doi:10.1074/jbc.m113.545921

Cited by 13 publications

(16 citation statements)

References 35 publications

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“…In addition to its pro-apoptotic effect in tumor cells, Chop also regulated cell death processes in primary myeloid populations. Deletion of Chop decreased apoptosis in liver and fat tissue macrophages from mice exposed to high fat diet (Grant et al, 2014; Malhi et al, 2013). Moreover, low numbers of apoptotic CD11b + cells were found in the intestinal mucosa of Ddit3 −/− mice undergoing colitis, which correlated with a decreased disease progression (Namba et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

The Stress-Response Sensor Chop Regulates the Function and Accumulation of Myeloid-Derived Suppressor Cells in Tumors

et al. 2014

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Summary Adaptation of malignant cells to the hostile milieu present in tumors is an important determinant for their survival and growth. However, the interaction between tumor-linked stress and anti-tumor immunity remains poorly characterized. Here, we show the critical role of the cellular stress sensor C/EBP-homologous protein (Chop) in the accumulation and immune inhibitory activity of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). MDSCs lacking Chop had decreased immune regulatory functions and showed the ability to prime T cell function and induce anti-tumor responses. Chop expression in MDSCs was induced by tumor-linked reactive oxygen and nitrogen species and regulated by the activating-transcription factor-4. Chop-deficient MDSCs displayed reduced signaling through CCAAT/enhancer-binding protein-β, leading to a decreased production of interleukin-6 (IL-6) and low expression phospho-STAT3. IL-6 over-expression restored immune suppressive activity of Chop-deficient MDSCs. These findings suggest the role of Chop in tumor-induced tolerance and the therapeutic potential of targeting Chop in MDSCs for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

The Stress-Response Sensor Chop Regulates the Function and Accumulation of Myeloid-Derived Suppressor Cells in Tumors

et al. 2014

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“…20 We and others have demonstrated that BM-derived cells, including macrophages, T cells and neutrophils, worked together to regulate the inflammatory environment and fibrosis. 4, 7, 8, 9, 21, 22, 23 ER stress can be induced by multiple stimuli and it was reported to be involved in various diseases, including cardiovascular diseases, 10 obesity, 13 AKI14 and so on. Although the role of ER stress in different diseases is different, we demonstrated that ER stress in BM-derived cells protected acute cardiac inflammation and injury in response to Ang II.…”

Section: Discussionmentioning

confidence: 99%

“…14 CHOP deficiency prevented unilateral ureteral obstruction-induced renal inflammation and fibrosis, 43 while inactivation of CHOP promoted obesity-associated inflammation. 13 Smooth muscle cells-CHOP-deficient mice displayed reduced proliferation in atherosclerosis. 44 However, CHOP-null mutation increased proliferation and reduced apoptosis within the islets of Leprdb/db mice.…”

Section: Discussionmentioning

confidence: 99%

“…All three upstream signaling pathways that mediate ER stress, including the inositol requiring kinase 1 α /X-box-binding protein 1, activating transcription factor (ATF)6, and protein kinase-like ER kinase/eukaryotic translation initiation factor 2/ATF4 pathways, intersect at the transcription factor C/EBP homologous protein (CHOP) to initiate apoptosis and inflammation. 11, 12 Previous studies have demonstrated that ER stress was involved in various diseases, including cardiovascular diseases, 10 obesity, 13 acute kidney injury (AKI) 14 and so on. But the role of ER stress in different diseases was different.…”

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confidence: 99%

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Endoplasmic reticulum stress in bone marrow-derived cells prevents acute cardiac inflammation and injury in response to angiotensin II

et al. 2016

Cell Death Dis

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Inflammation plays an important role in hypertensive cardiac injury. The endoplasmic reticulum (ER) stress pathway is involved in the inflammatory response. However, the role of ER stress in elevated angiotensin II (Ang II)-induced cardiac injury remains unclear. In this study, we investigated the role of ER stress in Ang II-induced hypertensive cardiac injury. Transcriptome analysis and quantitative real-time PCR showed that Ang II infusion in mice increased ER stress-related genes expression in the heart. C/EBP homologous protein (CHOP) deficiency, a key mediator of ER stress, increased infiltration of inflammatory cells, especially neutrophils, the production of inflammatory cytokines, chemokines in Ang II-infused mouse hearts. CHOP deficiency increased Ang II-induced cardiac fibrotic injury: (1) Masson trichrome staining showed increased fibrotic areas, (2) immunohistochemistry staining showed increased expression of α-smooth muscle actin, transforming growth factor β1 and (3) quantitative real-time PCR showed increased expression of collagen in CHOP-deficient mouse heart. Bone marrow transplantation experiments indicated that CHOP deficiency in bone marrow cells was responsible for Ang II-induced cardiac fibrotic injury. Moreover, TUNEL staining and flow cytometry revealed that CHOP deficiency decreased neutrophil apoptosis in response to Ang II. Taken together, our study demonstrated that hypertension induced ER stress after Ang II infusion. ER stress in bone marrow-derived cells protected acute cardiac inflammation and injury in response to Ang II.

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“…ER stress is essential for leukocyte generation, and deficiency of C/EBP homologous protein, a target of the PERK signaling pathway, leads to increased total myeloid subpopulations such as neutrophils and F4/80 + macrophages (20). There is no basal IRE1a activity for resting neutrophils (21).…”

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confidence: 99%

Endoplasmic Reticulum Stress of Neutrophils Is Required for Ischemia/Reperfusion–Induced Acute Lung Injury

Chen

Jia

et al. 2015

The Journal of Immunology

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Diverse clinical factors, including intestinal ischemia, contribute to acute lung injury (ALI), which has up to a 40% mortality rate. During the development of lung injury an immune response is elicited that exacerbates the lung insult. Neutrophils have been well studied in mediating the pulmonary insults through an assortment of mechanisms, such as release of granule contents and production of proinflammatory cytokines due to the overactivation of complement and cytokines. In this study, we found that enhanced endoplasmic reticulum (ER) stress was observed in infiltrated neutrophils in the early stage of an ALI mice model. In neutrophils, complement 5a (C5a) inspires strong ER stress through inositol-requiring kinase 1a and, to a less extent, the protein kinase R–like ER kinase signaling pathway. The granule release induced by C5a was ER stress mediated. Knowkdown of X-box–binding protein 1, a downstream signaling molecule of inositol-requiring kinase 1a, impaired granule release, based on myeloperoxidase production. Further analysis revealed that C5a induced ER stress by binding to C5a receptor in neutrophils. Using xbpf/f MRP8-cre mice in which X-box–binding protein 1 is deficient specifically in neutrophils and ER stress is deprived, we confirmed that ER stress in neutrophils was required for granule release in vivo and led to ALI, whereas dampening ER stress in neutrophils substantially alleviated ALI. Taken together, our results demonstrated that C5a receptor–mediated ER stress induced granule release in neutrophils, contributing to the development of ALI. This novel mechanism suggests a new potential therapeutic target in autophagy regulation for ALI.

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Inactivation of C/ebp Homologous Protein-driven Immune-Metabolic Interactions Exacerbate Obesity and Adipose Tissue Leukocytosis

Cited by 13 publications

References 35 publications

The Stress-Response Sensor Chop Regulates the Function and Accumulation of Myeloid-Derived Suppressor Cells in Tumors

The Stress-Response Sensor Chop Regulates the Function and Accumulation of Myeloid-Derived Suppressor Cells in Tumors

Endoplasmic reticulum stress in bone marrow-derived cells prevents acute cardiac inflammation and injury in response to angiotensin II

Endoplasmic Reticulum Stress of Neutrophils Is Required for Ischemia/Reperfusion–Induced Acute Lung Injury

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