Homeodomain-interacting Protein Kinase 2 Regulates NLRP3 Inflammasome Activation Through Endoplasmic Reticulum Stress in Septic Liver Injury

Overview

Journal J Int Med Res

Publisher Sage Publications

Specialty General Medicine

Date 2023 May 16

PMID 37190764

Authors

Lijun Cao

Min Wen

Zhiqiang Hu

Weihe Jia

Jiayan Lin

Bo Hu

Gang Wu

Shengchuang Tong

Qinglin Chen

Xingming Liu

Xuhao Weng

Affiliations

Soon will be listed here.

Abstract

Objective: Septic liver injury is a major burden for the clinical management of sepsis. Hepatocyte cell death plays a crucial pathophysiological role in sepsis. A recent study proposed that NLRP3 inflammasome-mediated pyroptosis participates in septic liver injury. Therefore, investigating the mechanism controlling this process may help manage sepsis.

Methods: We investigated the role of homeodomain-interacting protein kinase 2 (HIPK2) in regulating the NLRP3 inflammasome in vivo using mouse models and in vitro in primary hepatocytes.

Results: HIPK2 could improve liver injury and survival in a mouse model of sepsis. Overexpression of HIPK2 could suppress NLRP3 and caspase-1-p20 expression, while HIPK2 knockdown led to higher levels of these two molecules. Importantly, HIPK2 could suppress endoplasmic reticulum (ER) stress. Pharmacologically inhibiting ER stress could abolish activation of the NLRP3 inflammasome in hepatocytes with HIPK2 knockdown.

Conclusion: HIPK2 can regulate ER stress and NLRP3 inflammasome activation in the liver during sepsis, and HIPK2-mediated suppression of ER stress participates in regulating NLRP3 inflammasome activation. The present study highlights the role of HIPK2 in regulating the inflammasome in septic liver injury, which may serve as a target for managing sepsis.

References

Xu M, Jiang Z, Wang C, Li N, Bo L, Zha Y . Acetate attenuates inflammasome activation through GPR43-mediated Ca-dependent NLRP3 ubiquitination. Exp Mol Med. 2019; 51(7):1-13. PMC: 6802670. DOI: 10.1038/s12276-019-0276-5. View

Canabal J, Kramer D . Management of sepsis in patients with liver failure. Curr Opin Crit Care. 2008; 14(2):189-97. DOI: 10.1097/MCC.0b013e3282f6a435. View

Lebeaupin C, Vallee D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B . Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2018; 69(4):927-947. DOI: 10.1016/j.jhep.2018.06.008. View

Akaike Y, Kuwano Y, Nishida K, Kurokawa K, Kajita K, Kano S . Homeodomain-interacting protein kinase 2 regulates DNA damage response through interacting with heterochromatin protein 1γ. Oncogene. 2014; 34(26):3463-73. DOI: 10.1038/onc.2014.278. View

Al-Beiti M, Lu X . Expression of HIPK2 in cervical cancer: correlation with clinicopathology and prognosis. Aust N Z J Obstet Gynaecol. 2008; 48(3):329-36. DOI: 10.1111/j.1479-828X.2008.00874.x. View

Torrente L, Sanchez C, Moreno R, Chowdhry S, Cabello P, Isono K . Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses. Oncogene. 2017; 36(44):6204-6212. PMC: 5641449. DOI: 10.1038/onc.2017.221. View

Zeeshan H, Lee G, Kim H, Chae H . Endoplasmic Reticulum Stress and Associated ROS. Int J Mol Sci. 2016; 17(3):327. PMC: 4813189. DOI: 10.3390/ijms17030327. View

Yan Y, Jiang W, Spinetti T, Tardivel A, Castillo R, Bourquin C . Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity. 2013; 38(6):1154-63. DOI: 10.1016/j.immuni.2013.05.015. View

Yan J, Li S, Li S . The role of the liver in sepsis. Int Rev Immunol. 2014; 33(6):498-510. PMC: 4160418. DOI: 10.3109/08830185.2014.889129. View

10.

Torres S, Baulies A, Insausti-Urkia N, Alarcon-Vila C, Fucho R, Solsona-Vilarrasa E . Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure. Gastroenterology. 2019; 157(2):552-568. DOI: 10.1053/j.gastro.2019.04.023. View

11.

Feng Y, Zhou L, Sun X, Li Q . Homeodomain-interacting protein kinase 2 (HIPK2): a promising target for anti-cancer therapies. Oncotarget. 2017; 8(12):20452-20461. PMC: 5386776. DOI: 10.18632/oncotarget.14723. View

12.

Vivas W, Weis S . Tidy up - The unfolded protein response in sepsis. Front Immunol. 2022; 13:980680. PMC: 9632622. DOI: 10.3389/fimmu.2022.980680. View

13.

Yun S, Budatha M, Dahlman J, Coon B, Cameron R, Langer R . Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling. Nat Cell Biol. 2016; 18(10):1043-53. PMC: 5301150. DOI: 10.1038/ncb3405. View

14.

Zhang H, Wang W, Fang H, Yang Y, Li X, He J . GSK-3β inhibition attenuates CLP-induced liver injury by reducing inflammation and hepatic cell apoptosis. Mediators Inflamm. 2014; 2014:629507. PMC: 4265684. DOI: 10.1155/2014/629507. View

15.

Imberg-Kazdan K, Ha S, Greenfield A, Poultney C, Bonneau R, Logan S . A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells. Genome Res. 2013; 23(4):581-91. PMC: 3613576. DOI: 10.1101/gr.144774.112. View

16.

Han J, Kaufman R . The role of ER stress in lipid metabolism and lipotoxicity. J Lipid Res. 2016; 57(8):1329-38. PMC: 4959874. DOI: 10.1194/jlr.R067595. View

17.

Gao X, Guo S, Zhang S, Liu A, Shi L, Zhang Y . Matrine attenuates endoplasmic reticulum stress and mitochondrion dysfunction in nonalcoholic fatty liver disease by regulating SERCA pathway. J Transl Med. 2018; 16(1):319. PMC: 6245862. DOI: 10.1186/s12967-018-1685-2. View

18.

Ezpeleta M, Gabel K, Cienfuegos S, Kalam F, Lin S, Pavlou V . Effect of alternate day fasting combined with aerobic exercise on non-alcoholic fatty liver disease: A randomized controlled trial. Cell Metab. 2022; 35(1):56-70.e3. PMC: 9812925. DOI: 10.1016/j.cmet.2022.12.001. View

19.

Deshmukh H, Yeh T, Yu J, Sharma M, Perry A, Leonard J . High-resolution, dual-platform aCGH analysis reveals frequent HIPK2 amplification and increased expression in pilocytic astrocytomas. Oncogene. 2008; 27(34):4745-51. DOI: 10.1038/onc.2008.110. View

20.

Lei Y, Wan S, Liu H, Zhou H, Chen L, Yang Y . ARRB1 suppresses the activation of hepatic macrophages via modulating endoplasmic reticulum stress in lipopolysaccharide-induced acute liver injury. Cell Death Discov. 2021; 7(1):223. PMC: 8403172. DOI: 10.1038/s41420-021-00615-9. View