2. Academic Validation
  3. S100A8/A9-activated IFNγ+ NK cells trigger β-cell necroptosis in hepatitis B virus-associated liver cirrhosis

S100A8/A9-activated IFNγ+ NK cells trigger β-cell necroptosis in hepatitis B virus-associated liver cirrhosis

  • Cell Mol Life Sci. 2024 Aug 12;81(1):345. doi: 10.1007/s00018-024-05365-2.
Xuehui Li 1,  Liang Hong 1,  MingHui Ru 1,  Rui Cai 1,  Yuting Meng 1,  Baohua Wang 2,  Hongyan Diao 3,  Lanjuan Li 4 5,  Zhongwen Wu 6
Affiliations

Affiliations

  • 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
  • 2 Department of Ultrasound, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, 310000, People's Republic of China.
  • 3 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China. diaohy@zju.edu.cn.
  • 4 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China. ljli@zju.edu.cn.
  • 5 Jinan Microecological Biomedicine Shandong Laboratory, Jinan, People's Republic of China. ljli@zju.edu.cn.
  • 6 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China. wuzhongwen@zju.edu.cn.
PMID: 39133305 DOI: 10.1007/s00018-024-05365-2
Abstract

Background and aims: Hepatitis B virus (HBV)-associated liver cirrhosis (LC), a common condition with high incidence and mortality rates, is often associated with diabetes mellitus (DM). However, the molecular mechanisms underlying impaired glucose regulation during HBV-associated LC remain unclear.

Methods: Data from 63 patients with LC and 62 patients with LC-associated DM were analysed. Co-culture of NK cells and islet β cell lines were used to study the glucose regulation mechanism. A mouse model of LC was used to verify the effect of S100A8/A9 on the glucose regulation.

Results: Higher levels of interferon (IFN)-γ derived from natural killer (NK) cells and lower levels of Insulin emerged in the peripheral blood of patients with both LC and DM compared with those from patients with LC only. IFN-γ derived from NK cells facilitated β cell Necroptosis and impaired Insulin production. Furthermore, S100A8/A9 elevation in patients with both LC and DM was found to upregulate IFN-γ production in NK cells. Consistently, in the mouse model for LC, mice treated with carbon tetrachloride (CCL4) and S100A8/A9 exhibited increased blood glucose, impaired Insulin production, increased IFN-γ, and increased β cells Necroptosis compared with those treated with CCL4. Mechanistically, S100A8/A9 activated the p38 MAPK pathway to increase IFN-γ production in NK cells. These effects were diminished after blocking RAGE.

Conclusion: Together, the data indicate that IFN-γ produced by NK cells induces β cell Necroptosis via the S100A8/A9-RAGE-p38 MAPK axis in patients with LC and DM. Reduced levels of S100A8/A9, NK cells, and IFN-γ could be valuable for the treatment of LC with DM. Accumulation of S100A8/A9 in patients with LC may indicate the emergence of DM.

Keywords

Diabetes mellitus; Liver cirrhosis; Natural killer cells; Necroptosis; S100A8/A9.

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