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IL-33/ST2 signaling in liver transplantation

Cellular & Molecular Immunology volume 18, pages 761–763 (2021)Cite this article

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In a study published in Cellular & Molecular Immunology, we described a novel mechanism by which IL-33 drives hepatic fibrosis through the MAPK pathway. The study demonstrated that hepatocyte-derived IL-33 is elevated upon bile duct ligation (BDL)-induced liver injury and fibrogenesis and activates hepatic stellate cells in a JNK/ERK/p38-dependent manner.1 As a member of the IL-1 family, IL-33 promotes CD4+ T helper 2 (Th2) cytokines but suppresses Th1 cytokines via IL-4, IL-6, and IL-10 production. Th cells are central to the adaptive immune response activation and suppression of B cells and cytotoxic T cells by releasing different types of cytokines in tissues. These regulations are essential for immune homeostasis and suppression of excessive response against self-antigens to prevent autoimmunity. Liver transplantation surgery is a complex procedure accompanied by graft or major organ ischemia-reperfusion, life-threatening hemorrhage, and homeostasis instability. Recipients with viral hepatitis, alcoholic hepatitis, or hepatic carcinoma could have underlying liver inflammation, and increased secretion of cytokines may result in graft rejection. This commentary will focus on the crucial role of IL-33/ST2 signaling in liver transplantation and highlight the potential of intervening in ST2/IL-33 signaling as a treatment option.

Liver ischemia-reperfusion is an inevitable process in organ procurement and transplantation, in which the blood supply is excluded and reconstructed, and free oxygen radicals and proinflammatory cytokines are produced, resulting in a magnified inflammatory response in grafts and recipients. Initial research showed that IL-33 protein expression increases within 4 h of reperfusion and remains elevated for up to 8 h. Recombinant IL-33 reduces hepatocyte cell death as a result of increased NF-κB, p38, cyclin D1 activation, and Bcl-2 expression in hepatocytes.3 Sakai et al. also demonstrated that IL‐33 may have direct protective effects on hepatocytes, since ST2 is detected only in hepatocytes but not in the specialized liver macrophages, Kupffer’s cells. Núñez et al. showed that upregulated IL-33 predicts diminished liver damage in a steatosis-associated liver I/R model.4 Yazdani et al. found that liver ischemia and reperfusion injury cause the formation of neutrophil extracellular traps (NETs) that contribute to tissue damage in liver surgery. Liver sinusoidal endothelial cells release IL-33, which potentially promotes NET formation during liver I/R injury, exacerbating inflammatory cascades and inflammation.5 The discordance of these findings may result from the use of different schedules of IL-33 administration. Alternately, pretreatment with IL-33 may stimulate ST2-positive innate immune cells, which might eliminate further immune responses and liver damage. Thus, to understand the comprehensive function of IL-33, more investigations focusing on the shift in the immune microenvironment are required.

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Acknowledgements

This work was suppo rted by grants from the National Natural Science Foundation of China (81972675 to Z.T. and 81930086 to B.S.).

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  1. Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

    Zhongming Tan

  2. Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210029, Jiangsu, China

    Beicheng Sun

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Correspondence to Beicheng Sun.

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Tan, Z., Sun, B. IL-33/ST2 signaling in liver transplantation. Cell Mol Immunol 18, 761–763 (2021). https://doi.org/10.1038/s41423-020-0418-7

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