IL-17 Imbalance Promotes the Pyroptosis in Immune-Mediated Liver Injury Through STAT3-IFI16 Axis

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Abstract

Autoimmune hepatitis (AIH) affects all age group and occurs mainly in women. Pyroptosis is a novel programmed cell death featured with cell bursting and release of proinflammatory cytokines. A deeper understanding of AIH pathogenesis will contribute to novel therapy for AIH patients. Here, we aimed to investigate the role of IL-17 in immune-mediated liver injury. The levels of cytokines were measured by ELISA, and mRNA levels of STAT3 and IFN gamma-inducible protein 16 (IFI16) were detected by PCR. Expressions of STAT3, IFI16, gasdermin D and cleaved caspase-1 were measured by western-blotting. Immunohistochemical staining and transmission electron microscopy were applied to evaluate liver histopathological changes of the treated mice. Our results showed that the levels of IFI16 was increased in hepatocytes treated with IL-17 protein, and further elevated after STAT3-overexpressed (STAT3-OE) lentivirus treatment. The levels of IFI16 were reduced in hepatocytes treated with IL-17 neutralizing Ab (nAb), but were significantly increased after STAT3-OE treatment. Pyroptosis was observed in hepatocytes treated with IL-17 protein, and further cell damage was observed after STAT3-OE lentivirus treatment. Liver damage was alleviated in mice treated with IL-17 nAb, however sever damage was experienced after STAT3-OE lentivirus treatment. A binding interaction between IFI16 and STAT3 was detected in IL-17 treated hepatocytes. Glutathione transaminase activity was enhanced in concanavalin A-induced AIH mice compared to the control group (p<0.01). IL-17 plays an important role in activating STAT3 and up-regulating IFI16, which may promote the pyroptosis in AIH-related liver injury through STAT3-IFI16 axis.

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Cancer statistics, 2022

Rebecca Siegel, Kimberly D Miller, Hannah Fuchs … (2022)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes. Incidence data (through 2018) were collected by the Surveillance, Epidemiology, and End Results program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2019) were collected by the National Center for Health Statistics. In 2022, 1,918,030 new cancer cases and 609,360 cancer deaths are projected to occur in the United States, including approximately 350 deaths per day from lung cancer, the leading cause of cancer death. Incidence during 2014 through 2018 continued a slow increase for female breast cancer (by 0.5% annually) and remained stable for prostate cancer, despite a 4% to 6% annual increase for advanced disease since 2011. Consequently, the proportion of prostate cancer diagnosed at a distant stage increased from 3.9% to 8.2% over the past decade. In contrast, lung cancer incidence continued to decline steeply for advanced disease while rates for localized-stage increased suddenly by 4.5% annually, contributing to gains both in the proportion of localized-stage diagnoses (from 17% in 2004 to 28% in 2018) and 3-year relative survival (from 21% to 31%). Mortality patterns reflect incidence trends, with declines accelerating for lung cancer, slowing for breast cancer, and stabilizing for prostate cancer. In summary, progress has stagnated for breast and prostate cancers but strengthened for lung cancer, coinciding with changes in medical practice related to cancer screening and/or treatment. More targeted cancer control interventions and investment in improved early detection and treatment would facilitate reductions in cancer mortality.

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Hepatocellular carcinoma

Josep Llovet, Robin Kate Kelley, Augusto Villanueva … (2021)

Liver cancer remains a global health challenge, with an estimated incidence of >1 million cases by 2025. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases. Infection by hepatitis B virus and hepatitis C virus are the main risk factors for HCC development, although non-alcoholic steatohepatitis associated with metabolic syndrome or diabetes mellitus is becoming a more frequent risk factor in the West. Moreover, non-alcoholic steatohepatitis-associated HCC has a unique molecular pathogenesis. Approximately 25% of all HCCs present with potentially actionable mutations, which are yet to be translated into the clinical practice. Diagnosis based upon non-invasive criteria is currently challenged by the need for molecular information that requires tissue or liquid biopsies. The current major advancements have impacted the management of patients with advanced HCC. Six systemic therapies have been approved based on phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) and three additional therapies have obtained accelerated FDA approval owing to evidence of efficacy. New trials are exploring combination therapies, including checkpoint inhibitors and tyrosine kinase inhibitors or anti-VEGF therapies, or even combinations of two immunotherapy regimens. The outcomes of these trials are expected to change the landscape of HCC management at all evolutionary stages.

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Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores.

Xing-Xing Liu, Zhibin Zhang, Jianbin Ruan … (2016)

Inflammatory caspases (caspases 1, 4, 5 and 11) are activated in response to microbial infection and danger signals. When activated, they cleave mouse and human gasdermin D (GSDMD) after Asp276 and Asp275, respectively, to generate an N-terminal cleavage product (GSDMD-NT) that triggers inflammatory death (pyroptosis) and release of inflammatory cytokines such as interleukin-1β. Cleavage removes the C-terminal fragment (GSDMD-CT), which is thought to fold back on GSDMD-NT to inhibit its activation. However, how GSDMD-NT causes cell death is unknown. Here we show that GSDMD-NT oligomerizes in membranes to form pores that are visible by electron microscopy. GSDMD-NT binds to phosphatidylinositol phosphates and phosphatidylserine (restricted to the cell membrane inner leaflet) and cardiolipin (present in the inner and outer leaflets of bacterial membranes). Mutation of four evolutionarily conserved basic residues blocks GSDMD-NT oligomerization, membrane binding, pore formation and pyroptosis. Because of its lipid-binding preferences, GSDMD-NT kills from within the cell, but does not harm neighbouring mammalian cells when it is released during pyroptosis. GSDMD-NT also kills cell-free bacteria in vitro and may have a direct bactericidal effect within the cytosol of host cells, but the importance of direct bacterial killing in controlling in vivo infection remains to be determined.

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Author and article information

Journal

Journal ID (nlm-ta): Immune Netw

Journal ID (iso-abbrev): Immune Netw

Journal ID (publisher-id): IN

Title: Immune Network

Publisher: The Korean Association of Immunologists

ISSN (Print): 1598-2629

ISSN (Electronic): 2092-6685

Publication date Collection: December 2023

Publication date (Electronic): 11 December 2023

Volume: 23

Issue: 6

Electronic Location Identifier: e46

Affiliations

[1 ]Department of Clinical Laboratory, Affiliated Hospital of Shaoxing University, Shaoxing 312020, China.

[2 ]State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310027, China.

[3 ]Hangzhou Cosmos Wisdom Mass Spectrometry Center of Zhejiang University Medical School, Hangzhou 311200, China.

[4 ]Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou 310016, China.

Author notes

Correspondence to Wenfang Xu. Department of Clinical Laboratory, Affiliated Hospital of Shaoxing University, 999 Zhongxing South Road, Yuecheng District, Shaoxing 312020, China. 0052019050@ 123456usx.edu.cn

Correspondence to Hong Wang. Hangzhou Cosmos Wisdom Mass Spectrometry Center of Zhejiang University Medical School, 198 Qidi Road, Xiaoshan District, Hangzhou 311200, China. wh@ 123456cwmda.com

^†Wenfang Xu and Yanan Wang contributed equally to this work.

Author information

Wenfang Xu https://orcid.org/0009-0000-4909-4667

Yanan Wang https://orcid.org/0000-0002-9936-049X

Changzhong Jin https://orcid.org/0000-0001-6329-1739

Weiyang Zhang https://orcid.org/0009-0007-3161-336X

Jiangnan Chen https://orcid.org/0000-0002-1041-9927

Xuefang Chen https://orcid.org/0000-0003-4468-4195

Junli Gao https://orcid.org/0009-0005-8447-0097

Junshun Gao https://orcid.org/0009-0001-8437-5023

Hong Wang https://orcid.org/0000-0002-0382-9936

Article

DOI: 10.4110/in.2023.23.e46

PMC ID: 10767549

PubMed ID: 38188602

SO-VID: d1ec60b5-6abb-4ad8-8f2a-814cab1d7a2e

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 03 August 2023

Date revision received : 22 November 2023

Date accepted : 06 December 2023

Funding

Funded by: Science and Technology Department of Zhejiang Province, CrossRef https://doi.org/10.13039/501100008990;

Award ID: LGF20H100001

IL-17 Imbalance Promotes the Pyroptosis in Immune-Mediated Liver Injury Through STAT3-IFI16 Axis

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Most cited references 29

Cancer statistics, 2022

Hepatocellular carcinoma

Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores.

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