IRE1α aggravates ischemia reperfusion injury of fatty liver by regulating phenotypic transformation of kupffer cells

Yang, Faji; Wang, Shuai; Liu, Yang; Zhou, Yuan; Shang, Longcheng; Feng, Min; Yuan, Xianwen; Zhu, Wei; Shi, Xiaolei

doi:10.1016/j.freeradbiomed.2018.06.043

Cited by 34 publications

(34 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(17) Similarly, both IRE1α and CHOP have been found to suppress M2-like polarization of liver-resident macrophages, leading to excessive inflammation and exacerbation of liver injury. (16,18) In the present study, VDR deficiency increased expression of proinflammatory activation markers and decreased induction of alternative macrophage activation markers in the liver. In vitro experiments demonstrate that VDR activation inhibits proinflammatory activation and facilitates alternative polarization in BMDMs treated with ER-stress CM.…”

Section: Discussionsupporting

confidence: 53%

“…In contrast, macrophage‐specific deletion of IRE1α restores the M2 polarization and decreases levels of proinflammatory cytokines . Similarly, both IRE1α and CHOP have been found to suppress M2‐like polarization of liver‐resident macrophages, leading to excessive inflammation and exacerbation of liver injury . In the present study, VDR deficiency increased expression of proinflammatory activation markers and decreased induction of alternative macrophage activation markers in the liver.…”

Section: Discussioncontrasting

confidence: 40%

“…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 . However, the interactions between HCs and macrophages during ER stress in both cell types’ response remain unclear.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 53%

Section: Discussioncontrasting

confidence: 40%

mentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Despite regulating obesity and the cystic fibrosis, the roles of macrophage in liver diseases are closely linked to ER stress. STAT1 and STAT6 pathways are involved in the inhibition of M1 polarization and the promotion of M2 polarization in NAFLD (84,122). As expected, knockdown of PERK alters STAT1 and STAT6 pathway in macrophage to increase NAFLD (86).…”

Section: Macrophagessupporting

confidence: 70%

The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities

Song

Riesenberg

et al. 2020

Front. Immunol.

View full text Add to dashboard Cite

The endoplasmic reticulum (ER) is an organelle equipped with mechanisms for proper protein folding, trafficking, and degradation to maintain protein homeostasis in the secretory pathway. As a defense mechanism, perturbation of ER proteostasis by ER stress agents activates a cascade of signaling pathways from the ER to the nucleus known as unfolded protein response (UPR). The primary goal of UPR is to induce transcriptional and translational programs to restore ER homeostasis for cell survival. As such, defects in UPR signaling have been implicated as a key contributor to multiple diseases including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer. Growing evidence support the critical role of ER stress in regulating the fate as well as the magnitude of the immune response. Moreover, the availability of multiple UPR pharmacological inhibitors raises the hope that targeting UPR can be a new strategy for immune modulation and immunotherapy of diseases. This paper reviews the principal mechanisms by which ER stress affects immune cell biology and function, with a focus of discussion on UPR-associated immunopathology and the development of potential ER stress-targeted therapeutics.Frontiers in Immunology | www.frontiersin.org Conflict of Interest: ZL serves as member of scientific advisory board for Alphamab and Henlius Biotech and has a sponsored research agreement with Bristol-Myers Squibb.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

show abstract

“…Western blotting was performed as previously described (Yang et al, ). Protein was extracted using lysis buffer (KeyGEN BioTECH, Nanjing) and was separated by SDS‐PAGE (12% or 10% gel) and transferred onto nitrocellulose membranes.…”

Section: Methodsmentioning

confidence: 99%

Puerarin protects against high‐fat high‐sucrose diet‐induced non‐alcoholic fatty liver disease by modulating PARP‐1/PI3K/AKT signaling pathway and facilitating mitochondrial homeostasis

Wang

Yang

Shang

et al. 2019

Phytotherapy Research

Self Cite

View full text Add to dashboard Cite

As yet, there was no effective pharmacological therapy approved for non‐alcoholic fatty liver disease (NAFLD). Here, we aimed to evaluate the therapeutic potential of puerarin against NAFLD and explored the underlying mechanisms. C57BL/6J mice were fed with a high‐fat high‐sucrose (HFHS) diet with or without puerarin coadministration intragastrically. The levels of hepatocellular injury, steatosis, fibrosis, and mitochondrial and metabolism alteration were detected. First, puerarin ameliorated histopathologic abnormalities due to HFHS. We observed a marked increase in hepatic lipid content, inflammation, and fibrosis level, which were attenuated by puerarin. Possible mechanisms were related to puerarin‐mediated activation of PI3K/AKT pathway and further improvement in fatty acid metabolism. Puerarin restored the NAD+ content and beneficially affected the hepatic mitochondrial function, which attenuated HFHS‐induced steatosis and metabolic disturbances. Finally, hepatic PARP‐1 was activated due to excessive fat intake. Puerarin attenuated the PARP‐1 expression in HFHS‐fed mice, and PJ34, the PARP inhibitor, could mimic these protections of puerarin. However, pharmacological inhibition of PI3K disabled the protection of puerarin or PJ34 toward NAD+ refilling and mitochondrial homeostasis. In conclusion, our findings indicated that puerarin could be a promising and practical therapeutic strategy in NAFLD through modulating PARP‐1/PI3K/AKT signaling pathway and further facilitating mitochondrial function.

show abstract

IRE1α aggravates ischemia reperfusion injury of fatty liver by regulating phenotypic transformation of kupffer cells

Cited by 34 publications

References 55 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

The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities

Puerarin protects against high‐fat high‐sucrose diet‐induced non‐alcoholic fatty liver disease by modulating PARP‐1/PI3K/AKT signaling pathway and facilitating mitochondrial homeostasis

Contact Info

Product

Resources

About