Research progress of NETs in hepatic ischemia<b>-</b>reperfusion injury_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

CHEN Rude ^1,2 , LUO Zhulin ² , CHENG Long ² ,  WANG Tao ^1,2

1. Department of Clinical Medicine, North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;
2. Department of General Surgery, The General Hospital of Western Theater Command, Chengdu 610000, P. R. China;

Corresponding author：

WANG Tao, Email: watopo@163.com

Keywords：

hepatic ischemia-reperfusion injury; neutrophil extracellular traps; aseptic inflammatory response

DOI：

10.7507/1007-9424.202310086

Video：

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Objective To summarize the mechanism of neutrophil extracellular traps (NETs) in hepatic ischemia-reperfusion injury (HIRI) and the research progress in targeting NETs to reduce HIRI, providing valuable reference for reducing HIRI. Method The related literatures at home and abroad about the role of NETs in the pathogenesis of HIRI and target NETs to alleviate HIRI were retrieved and reviewed. Results HIRI usually appeared in the process of liver surgery and was a common clinical problem, which occured in situations such as liver surgery, organ transplantation, liver ischemia and so on. This kind of injury would lead to tissue necrosis, inflammatory response and oxidative stress, which was a major cause of hepatic dysfunction and multiple organ failure after hepatic surgery, greatly increases the complications and mortality after hepatic surgery. NETs played a crucial role in the aseptic inflammatory response induced by hepatic ischemia/reperfusion. During hepatic ischemia-reperfusion, neutrophils promoted inflammatory cascade reactions and cytokine storms by forming NETs, exacerbating damage caused by hepatic ischemia-reperfusion. At present, some experimental and clinical studies had shown that inhibiting the formation of NETs or eliminating the formed NETs could alleviate the hepatic ischemia-reperfusion injury and improve the prognosis. Conclusions Targeting NETs may become a new method for treating hepatic ischemia-reperfusion injury. In the future, it is foreseeable that more experiments and clinical trials will be conducted on targeted NETs for the treatment of hepatic ischemia-reperfusion injury. And gradually establish more comprehensive and effective treatment strategies, thereby providing new ways to improve the prognosis of hepatic surgery patients in clinical practice.

Citation： CHEN Rude, LUO Zhulin, CHENG Long, WANG Tao. Research progress of NETs in hepatic ischemia-reperfusion injury. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2024, 31(3): 373-378. doi: 10.7507/1007-9424.202310086 Copy

1.	Hirao H, Nakamura K, Kupiec-Weglinski JW. B Liver ischaemia-reperfusion injury: a new understanding of the role of innate immunity. Nat Rev Gastroenterol Hepatol, 2022, 19(4): 239-256.
2.	Kaltenmeier C, Yazdani HO, Handu S, et al. The role of neutrophils as a driver in hepatic ischemia-reperfusion injury and cancer growth. Front Immunol, 2022, 13: 887565.
3.	Gracia-Sancho J, Caparrós E, Fernández-Iglesias A, et al. Role of liver sinusoidal endothelial cells in liver diseases. Nat Rev Gastroenterol Hepatol, 2021, 18(6): 411-431.
4.	Liu Y, Qin X, Lei Z, et al. Diphenyleneiodonium ameliorates acute liver rejection during transplantation by inhibiting neutrophil extracellular traps formation in vivo. Transpl Immunol, 2021, 68: 101434.
5.	Kaltenmeier C, Yazdani HO, Morder K, et al. Neutrophil extracellular traps promote T cell exhaustion in the tumor microenvironment. Front Immunol, 2021, 12: 785222.
6.	Roh JS, Sohn DH. Damage-associated molecular patterns in inflammatory diseases. Immune Netw, 2018, 18(4): e27.
7.	Oliveira THC, Marques PE, Proost P, et al. Neutrophils: a cornerstone of liver ischemia and reperfusion injury. Lab Invest, 2018, 98(1): 51-62.
8.	Kaltenmeier C, Wang R, Popp B, et al. Role of immuno-inflammatory signals in liver ischemia-reperfusion injury. Cells, 2022, 11(14): 2222.
9.	Thiam HR, Wong SL, Wagner DD, et al. cellular mechanisms of NETosis. Annu Rev Cell Dev Biol, 2020, 36: 191-218.
10.	Vorobjeva NV, Chernyak BV. NETosis: molecular mechanisms, role in physiology and pathology. Biochemistry (Mosc), 2020, 85(10): 1178-1190.
11.	Herre M, Cedervall J, Mackman N, et al. Neutrophil extracellular traps in the pathology of cancer and other inflammatory diseases. Physiol Rev, 2023, 103(1): 277-312.
12.	Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol, 2018, 18(2): 134-147.
13.	Bonaventura A, Liberale L, Carbone F, et al. The pathophysiological role of neutrophil extracellular traps in inflammatory diseases. Thromb Haemost, 2018, 118(1): 6-27.
14.	de Bont CM, Boelens WC, Pruijn GJM. NETosis, complement, and coagulation: a triangular relationship. Cell Mol Immunol, 2019, 16(1): 19-27.
15.	Sorvillo N, Cherpokova D, Martinod K, et al. Extracellular DNA NET-works with dire consequences for health. Circ Res, 2019, 125(4): 470-488.
16.	Huang H, Tohme S, Al-Khafaji AB, et al. Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology, 2015, 62(2): 600-614.
17.	Dar WA, Sullivan E, Bynon JS, et al. Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms. Liver Int, 2019, 39(5): 788-801.
18.	Dai Q, Jiang W, Liu H, et al. Kupffer cell-targeting strategy for the protection of hepatic ischemia/reperfusion injury. Nanotechnology, 2021, 32(26).
19.	Ye L, He S, Mao X, et al. Effect of hepatic macrophage polarization and apoptosis on liver ischemia and reperfusion injury during liver transplantation. Front Immunol, 2020, 11: 1193.
20.	Yazdani HO, Kaltenmeier C, Morder K, et al. Exercise training decreases hepatic injury and metastases through changes in immune response to liver ischemia/reperfusion in mice. Hepatology, 2021, 73(6): 2494-2509.
21.	Su L, Li N, Tang H, et al. Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells. Cell Death Dis, 2018, 9(3): 323.
22.	Liu A, Fang H, Dirsch O, et al. Oxidation of HMGB1 causes attenuation of its pro-inflammatory activity and occurs during liver ischemia and reperfusion. PLoS One, 2012, 7(4): e35379.
23.	Colomina MJ, Méndez E, Sabate A. Altered fibrinolysis during and after surgery. Semin Thromb Hemost, 2021, 47(5): 512-519.
24.	Mandel J, Casari M, Stepanyan M, et al. Beyond hemostasis: platelet innate immune interactions and thromboinflammation. Int J Mol Sci, 2022, 23(7): 3868.
25.	Granai M, Warm V, Vogelsberg A, et al. Impact of P-selectin-PSGL-1 axis on platelet-endothelium-leukocyte interactions in fatal COVID-19. Lab Invest, 2023, 103(8): 100179.
26.	Liu Y, Yan P, Bin Y, et al. Neutrophil extracellular traps and complications of liver transplantation. Front Immunol, 2022, 13: 1054753.
27.	Carminita E, Crescence L, Panicot-Dubois L, et al. Role of neutrophils and NETs in animal models of thrombosis. Int J Mol Sci, 2022, 23(3): 1411.
28.	Kim SJ, Jenne CN. Role of platelets in neutrophil extracellular trap (NET) production and tissue injury. Semin Immunol, 2016, 28(6): 546-554.
29.	Poli V, Zanoni I. Neutrophil intrinsic and extrinsic regulation of NETosis in health and disease. Trends Microbiol, 2023, 31(3): 280-293.
30.	Zhang H, Goswami J, Varley P, et al. Hepatic surgical stress promotes systemic immunothrombosis that results in distant organ injury. Front Immunol, 2020, 1: 987.
31.	Tohme S, Yazdani HO, Sud V, et al. Computational analysis supports IL-17A as a central driver of neutrophil extracellular trap-mediated injury in liver ischemia reperfusion. J Immunol, 2019, 202(1): 268-277.
32.	Fernández L, Heredia N, Grande L, et al. Preconditioning protects liver and lung damage in rat liver transplantation: role of xanthine/xanthine oxidase. Hepatology, 2002, 36(3): 562-572.
33.	Liu Y, Qin X, Lei Z, et al. Tetramethylpyrazine inhibits neutrophil extracellular traps formation and alleviates hepatic ischemia/reperfusion injury in rat liver transplantation. Exp Cell Res, 2021, 406(1): 112719.
34.	Liu Y, Lei Z, Chai H, et al. Thrombomodulin-mediated Inhibition of neutrophil extracellular trap formation alleviates hepatic ischemia-reperfusion injury by blocking TLR4 in rats subjected to liver transplantation. Transplantation, 2022, 106(2): e126-e140.
35.	Kaltenmeier C, Simmons RL, Tohme S, et al. Neutrophil extracellular traps (NETs) in cancer metastasis. Cancers (Basel), 2021, 13(23): 6131.
36.	Duarte S, Matian P, Ma S, et al. Adeno-associated virus-mediated gene transfer of tissue inhibitor of metalloproteinases-1 impairs neutrophil extracellular trap formation and ameliorates hepatic ischemia and reperfusion injury. Am J Pathol, 2018, 188(8): 1820-1832.
37.	Yazdani HO, Roy E, Comerci AJ, et al. Neutrophil extracellular traps drive mitochondrial homeostasis in tumors to augment growth. Cancer Res, 2019, 79(21): 5626-5639.
38.	Tohme S, Yazdani HO, Liu Y, et al. Hypoxia mediates mitochondrial biogenesis in hepatocellular carcinoma to promote tumor growth through HMGB1 and TLR9 interaction. Hepatology, 2017, 66(1): 182-197.
39.	Tohme S, Yazdani HO, Al-Khafaji AB, et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res, 2016, 76(6): 1367-1380.
40.	Jančinová V, Pažoureková S, Lucová M, et al. Selective inhibition of extracellular oxidants liberated from human neutrophils—A new mechanism potentially involved in the anti-inflammatory activity of hydroxychloroquine. Int Immunopharmacol, 2015, 28(1): 175-181.
41.	Zhang S, Zhang Q, Wang F, et al. Hydroxychloroquine inhibiting neutrophil extracellular trap formation alleviates hepatic ischemia/reperfusion injury by blocking TLR9 in mice. Clin Immunol, 2020 Jul: 216: 108461.
42.	Lu T, Zhang J, Cai J, et al. Extracellular vesicles derived from mesenchymal stromal cells as nanotherapeutics for liver ischaemia-reperfusion injury by transferring mitochondria to modulate the formation of neutrophil extracellular traps. Biomaterials, 2022, 284: 121486.

1. Hirao H, Nakamura K, Kupiec-Weglinski JW. B Liver ischaemia-reperfusion injury: a new understanding of the role of innate immunity. Nat Rev Gastroenterol Hepatol, 2022, 19(4): 239-256.
2. Kaltenmeier C, Yazdani HO, Handu S, et al. The role of neutrophils as a driver in hepatic ischemia-reperfusion injury and cancer growth. Front Immunol, 2022, 13: 887565.
3. Gracia-Sancho J, Caparrós E, Fernández-Iglesias A, et al. Role of liver sinusoidal endothelial cells in liver diseases. Nat Rev Gastroenterol Hepatol, 2021, 18(6): 411-431.
4. Liu Y, Qin X, Lei Z, et al. Diphenyleneiodonium ameliorates acute liver rejection during transplantation by inhibiting neutrophil extracellular traps formation in vivo. Transpl Immunol, 2021, 68: 101434.
5. Kaltenmeier C, Yazdani HO, Morder K, et al. Neutrophil extracellular traps promote T cell exhaustion in the tumor microenvironment. Front Immunol, 2021, 12: 785222.
6. Roh JS, Sohn DH. Damage-associated molecular patterns in inflammatory diseases. Immune Netw, 2018, 18(4): e27.
7. Oliveira THC, Marques PE, Proost P, et al. Neutrophils: a cornerstone of liver ischemia and reperfusion injury. Lab Invest, 2018, 98(1): 51-62.
8. Kaltenmeier C, Wang R, Popp B, et al. Role of immuno-inflammatory signals in liver ischemia-reperfusion injury. Cells, 2022, 11(14): 2222.
9. Thiam HR, Wong SL, Wagner DD, et al. cellular mechanisms of NETosis. Annu Rev Cell Dev Biol, 2020, 36: 191-218.
10. Vorobjeva NV, Chernyak BV. NETosis: molecular mechanisms, role in physiology and pathology. Biochemistry (Mosc), 2020, 85(10): 1178-1190.
11. Herre M, Cedervall J, Mackman N, et al. Neutrophil extracellular traps in the pathology of cancer and other inflammatory diseases. Physiol Rev, 2023, 103(1): 277-312.
12. Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol, 2018, 18(2): 134-147.
13. Bonaventura A, Liberale L, Carbone F, et al. The pathophysiological role of neutrophil extracellular traps in inflammatory diseases. Thromb Haemost, 2018, 118(1): 6-27.
14. de Bont CM, Boelens WC, Pruijn GJM. NETosis, complement, and coagulation: a triangular relationship. Cell Mol Immunol, 2019, 16(1): 19-27.
15. Sorvillo N, Cherpokova D, Martinod K, et al. Extracellular DNA NET-works with dire consequences for health. Circ Res, 2019, 125(4): 470-488.
16. Huang H, Tohme S, Al-Khafaji AB, et al. Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology, 2015, 62(2): 600-614.
17. Dar WA, Sullivan E, Bynon JS, et al. Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms. Liver Int, 2019, 39(5): 788-801.
18. Dai Q, Jiang W, Liu H, et al. Kupffer cell-targeting strategy for the protection of hepatic ischemia/reperfusion injury. Nanotechnology, 2021, 32(26).
19. Ye L, He S, Mao X, et al. Effect of hepatic macrophage polarization and apoptosis on liver ischemia and reperfusion injury during liver transplantation. Front Immunol, 2020, 11: 1193.
20. Yazdani HO, Kaltenmeier C, Morder K, et al. Exercise training decreases hepatic injury and metastases through changes in immune response to liver ischemia/reperfusion in mice. Hepatology, 2021, 73(6): 2494-2509.
21. Su L, Li N, Tang H, et al. Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells. Cell Death Dis, 2018, 9(3): 323.
22. Liu A, Fang H, Dirsch O, et al. Oxidation of HMGB1 causes attenuation of its pro-inflammatory activity and occurs during liver ischemia and reperfusion. PLoS One, 2012, 7(4): e35379.
23. Colomina MJ, Méndez E, Sabate A. Altered fibrinolysis during and after surgery. Semin Thromb Hemost, 2021, 47(5): 512-519.
24. Mandel J, Casari M, Stepanyan M, et al. Beyond hemostasis: platelet innate immune interactions and thromboinflammation. Int J Mol Sci, 2022, 23(7): 3868.
25. Granai M, Warm V, Vogelsberg A, et al. Impact of P-selectin-PSGL-1 axis on platelet-endothelium-leukocyte interactions in fatal COVID-19. Lab Invest, 2023, 103(8): 100179.
26. Liu Y, Yan P, Bin Y, et al. Neutrophil extracellular traps and complications of liver transplantation. Front Immunol, 2022, 13: 1054753.
27. Carminita E, Crescence L, Panicot-Dubois L, et al. Role of neutrophils and NETs in animal models of thrombosis. Int J Mol Sci, 2022, 23(3): 1411.
28. Kim SJ, Jenne CN. Role of platelets in neutrophil extracellular trap (NET) production and tissue injury. Semin Immunol, 2016, 28(6): 546-554.
29. Poli V, Zanoni I. Neutrophil intrinsic and extrinsic regulation of NETosis in health and disease. Trends Microbiol, 2023, 31(3): 280-293.
30. Zhang H, Goswami J, Varley P, et al. Hepatic surgical stress promotes systemic immunothrombosis that results in distant organ injury. Front Immunol, 2020, 1: 987.
31. Tohme S, Yazdani HO, Sud V, et al. Computational analysis supports IL-17A as a central driver of neutrophil extracellular trap-mediated injury in liver ischemia reperfusion. J Immunol, 2019, 202(1): 268-277.
32. Fernández L, Heredia N, Grande L, et al. Preconditioning protects liver and lung damage in rat liver transplantation: role of xanthine/xanthine oxidase. Hepatology, 2002, 36(3): 562-572.
33. Liu Y, Qin X, Lei Z, et al. Tetramethylpyrazine inhibits neutrophil extracellular traps formation and alleviates hepatic ischemia/reperfusion injury in rat liver transplantation. Exp Cell Res, 2021, 406(1): 112719.
34. Liu Y, Lei Z, Chai H, et al. Thrombomodulin-mediated Inhibition of neutrophil extracellular trap formation alleviates hepatic ischemia-reperfusion injury by blocking TLR4 in rats subjected to liver transplantation. Transplantation, 2022, 106(2): e126-e140.
35. Kaltenmeier C, Simmons RL, Tohme S, et al. Neutrophil extracellular traps (NETs) in cancer metastasis. Cancers (Basel), 2021, 13(23): 6131.
36. Duarte S, Matian P, Ma S, et al. Adeno-associated virus-mediated gene transfer of tissue inhibitor of metalloproteinases-1 impairs neutrophil extracellular trap formation and ameliorates hepatic ischemia and reperfusion injury. Am J Pathol, 2018, 188(8): 1820-1832.
37. Yazdani HO, Roy E, Comerci AJ, et al. Neutrophil extracellular traps drive mitochondrial homeostasis in tumors to augment growth. Cancer Res, 2019, 79(21): 5626-5639.
38. Tohme S, Yazdani HO, Liu Y, et al. Hypoxia mediates mitochondrial biogenesis in hepatocellular carcinoma to promote tumor growth through HMGB1 and TLR9 interaction. Hepatology, 2017, 66(1): 182-197.
39. Tohme S, Yazdani HO, Al-Khafaji AB, et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res, 2016, 76(6): 1367-1380.
40. Jančinová V, Pažoureková S, Lucová M, et al. Selective inhibition of extracellular oxidants liberated from human neutrophils—A new mechanism potentially involved in the anti-inflammatory activity of hydroxychloroquine. Int Immunopharmacol, 2015, 28(1): 175-181.
41. Zhang S, Zhang Q, Wang F, et al. Hydroxychloroquine inhibiting neutrophil extracellular trap formation alleviates hepatic ischemia/reperfusion injury by blocking TLR9 in mice. Clin Immunol, 2020 Jul: 216: 108461.
42. Lu T, Zhang J, Cai J, et al. Extracellular vesicles derived from mesenchymal stromal cells as nanotherapeutics for liver ischaemia-reperfusion injury by transferring mitochondria to modulate the formation of neutrophil extracellular traps. Biomaterials, 2022, 284: 121486.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research progress of NETs in hepatic ischemia-reperfusion injury

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