OX40 Expression in Neutrophils Promotes Hepatic Ischemia/reperfusion Injury

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2019 Nov 2

PMID 31672934

Citations 11

Authors

Hua Jin

Chunpan Zhang

Chengyang Sun

Xinyan Zhao

Dan Tian

Wen Shi

Yue Tian

Kai Liu

Guangyong Sun

Hufeng Xu

Dong Zhang

Affiliations

Soon will be listed here.

Abstract

Neutrophils play critical roles during the initial phase of hepatic ischemia/reperfusion injury (HIRI). However, the regulation of neutrophil activation, infiltration, and proinflammatory cytokine secretion has not been fully elucidated. In this study, we revealed that OX40 was expressed by neutrophils, its expression in neutrophils was time-dependently upregulated following HIRI, and Ox40 knockout markedly alleviated liver injury. Compared with wild-type neutrophils, the adoptive transfer of Ox40-/- neutrophils decreased HIRI in neutrophil-depleted Rag2/Il2rg-/- or Ox40-/- mice. Moreover, consistently, the in vitro experiments showed that Ox40 not only prolonged neutrophil survival but also promoted proinflammatory cytokines, ROS production, and even neutrophil chemotaxis. Further investigation demonstrated that the knockout of Ox40 in neutrophils inhibited NF-κB signaling via the TRAF1/2/4 and IKKα/IKKβ/IκBα pathways. OX40L and OX86 stimulation could enhance neutrophil activation and survival in vitro and in vivo. In conclusion, our study provides a new understanding of OX40, which is expressed not only in adaptive immune cells but also in innate immune cells, i.e., neutrophils, contributing to the activation and survival of neutrophils. These findings provide a novel potential therapeutic target for the prevention of HIRI during liver transplantation or hepatic surgery.

Citing Articles

OX40L-Armed Oncolytic Virus Boosts T-cell Response and Remodels Tumor Microenvironment for Pancreatic Cancer Treatment.

Liu S, Li F, Ma Q, Du M, Wang H, Zhu Y Theranostics. 2023; 13(12):4016-4029.

PMID: 37554264 PMC: 10405835. DOI: 10.7150/thno.83495.

Immune response associated with ischemia and reperfusion injury during organ transplantation.

Tang Q, Dong C, Sun Q Inflamm Res. 2022; 71(12):1463-1476.

PMID: 36282292 PMC: 9653341. DOI: 10.1007/s00011-022-01651-6.

Blood transcriptome analysis revealing aging gene expression profiles in red panda.

Luo J, Zhang L, Shen F, Luo L, Chen L, Fan Z PeerJ. 2022; 10:e13743.

PMID: 35898935 PMC: 9310792. DOI: 10.7717/peerj.13743.

The Role of Neutrophils as a Driver in Hepatic Ischemia-Reperfusion Injury and Cancer Growth.

Kaltenmeier C, Yazdani H, Handu S, Popp B, Geller D, Tohme S Front Immunol. 2022; 13:887565.

PMID: 35844608 PMC: 9284204. DOI: 10.3389/fimmu.2022.887565.

Progress and Prospects of Non-Canonical NF-κB Signaling Pathway in the Regulation of Liver Diseases.

Tao L, Ren X, Zhai W, Chen Z Molecules. 2022; 27(13).

PMID: 35807520 PMC: 9268066. DOI: 10.3390/molecules27134275.

References

Lewis N, Muthukumarana A, Fogal S, Corradini L, Stefanopoulos D, Adusumalli P . CCR1 plays a critical role in modulating pain through hematopoietic and non-hematopoietic cells. PLoS One. 2014; 9(8):e105883. PMC: 4149507. DOI: 10.1371/journal.pone.0105883. View

Song J, So T, Croft M . Activation of NF-kappaB1 by OX40 contributes to antigen-driven T cell expansion and survival. J Immunol. 2008; 180(11):7240-8. PMC: 2410213. DOI: 10.4049/jimmunol.180.11.7240. View

Quesnelle K, Bystrom P, Toledo-Pereyra L . Molecular responses to ischemia and reperfusion in the liver. Arch Toxicol. 2015; 89(5):651-7. DOI: 10.1007/s00204-014-1437-x. View

Webb G, Hirschfield G, Lane P . OX40, OX40L and Autoimmunity: a Comprehensive Review. Clin Rev Allergy Immunol. 2015; 50(3):312-32. DOI: 10.1007/s12016-015-8498-3. View

Lan P, Fan Y, Zhao Y, Lou X, Monsour H, Zhang X . TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury. J Clin Invest. 2017; 127(6):2222-2234. PMC: 5451219. DOI: 10.1172/JCI91075. View

Xie K, Xu L, Wu H, Liao H, Luo L, Liao M . OX40 expression in hepatocellular carcinoma is associated with a distinct immune microenvironment, specific mutation signature, and poor prognosis. Oncoimmunology. 2018; 7(4):e1404214. PMC: 5889283. DOI: 10.1080/2162402X.2017.1404214. View

Chou R, Kim N, Sadik C, Seung E, Lan Y, Byrne M . Lipid-cytokine-chemokine cascade drives neutrophil recruitment in a murine model of inflammatory arthritis. Immunity. 2010; 33(2):266-78. PMC: 3155777. DOI: 10.1016/j.immuni.2010.07.018. View

Tan S, Weninger W . Neutrophil migration in inflammation: intercellular signal relay and crosstalk. Curr Opin Immunol. 2016; 44:34-42. DOI: 10.1016/j.coi.2016.11.002. View

Evans D, Prell R, Thalhofer C, Hurwitz A, Weinberg A . Engagement of OX40 enhances antigen-specific CD4(+) T cell mobilization/memory development and humoral immunity: comparison of alphaOX-40 with alphaCTLA-4. J Immunol. 2001; 167(12):6804-11. DOI: 10.4049/jimmunol.167.12.6804. View

10.

Zhang J, Dong Z, Zhou R, Luo D, Wei H, Tian Z . Isolation of lymphocytes and their innate immune characterizations from liver, intestine, lung and uterus. Cell Mol Immunol. 2005; 2(4):271-80. View

11.

Zhai Y, Petrowsky H, Hong J, Busuttil R, Kupiec-Weglinski J . Ischaemia-reperfusion injury in liver transplantation--from bench to bedside. Nat Rev Gastroenterol Hepatol. 2012; 10(2):79-89. PMC: 3577927. DOI: 10.1038/nrgastro.2012.225. View

12.

Ishii N, Takahashi T, Soroosh P, Sugamura K . OX40-OX40 ligand interaction in T-cell-mediated immunity and immunopathology. Adv Immunol. 2010; 105:63-98. DOI: 10.1016/S0065-2776(10)05003-0. View

13.

Singel K, Segal B . NOX2-dependent regulation of inflammation. Clin Sci (Lond). 2016; 130(7):479-90. PMC: 5513728. DOI: 10.1042/CS20150660. View

14.

Adam A . Some mechanisms of the protective effect of ischemic preconditioning on rat liver ischemia-reperfusion injury. Int J Gen Med. 2014; 7:483-9. PMC: 4222984. DOI: 10.2147/IJGM.S66766. View

15.

Croft M . Control of immunity by the TNFR-related molecule OX40 (CD134). Annu Rev Immunol. 2010; 28:57-78. PMC: 2882161. DOI: 10.1146/annurev-immunol-030409-101243. View

16.

Strzepa A, Pritchard K, Dittel B . Myeloperoxidase: A new player in autoimmunity. Cell Immunol. 2017; 317:1-8. PMC: 5665680. DOI: 10.1016/j.cellimm.2017.05.002. View

17.

Robertson F, Fuller B, Davidson B . An Evaluation of Ischaemic Preconditioning as a Method of Reducing Ischaemia Reperfusion Injury in Liver Surgery and Transplantation. J Clin Med. 2017; 6(7). PMC: 5532577. DOI: 10.3390/jcm6070069. View

18.

Kolaczkowska E, Kubes P . Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013; 13(3):159-75. DOI: 10.1038/nri3399. View

19.

Kawamata S, Hori T, Imura A, Takaori-Kondo A, Uchiyama T . Activation of OX40 signal transduction pathways leads to tumor necrosis factor receptor-associated factor (TRAF) 2- and TRAF5-mediated NF-kappaB activation. J Biol Chem. 1998; 273(10):5808-14. DOI: 10.1074/jbc.273.10.5808. View

20.

Bilzer M, Roggel F, Gerbes A . Role of Kupffer cells in host defense and liver disease. Liver Int. 2006; 26(10):1175-86. DOI: 10.1111/j.1478-3231.2006.01342.x. View