Natural Killer Cells in Hepatic Ischemia-Reperfusion Injury

Abstract

Ischemia-reperfusion injury can be divided into two phases, including insufficient supply of oxygen and nutrients in the first stage and then organ injury caused by immune inflammation after blood flow recovery. Hepatic ischemia-reperfusion is an important cause of liver injury post-surgery, consisting of partial hepatectomy and liver transplantation, and a central driver of graft dysfunction, which greatly leads to complications and mortality after liver transplantation. Natural killer (NK) cells are the lymphocyte population mainly involved in innate immune response in the human liver. In addition to their well-known role in anti-virus and anti-tumor defense, NK cells are also considered to regulate the pathogenesis of liver ischemia-reperfusion injury under the support of more and more evidence recently. The infiltration of NK cells into the liver exacerbates the hepatic ischemia-reperfusion injury, which could be significantly alleviated after depletion of NK cells. Interestingly, NK cells may contribute to both liver graft rejection and tolerance according to their origins. In this article, we discussed the development of liver NK cells, their role in ischemia-reperfusion injury, and strategies of inhibiting NK cell activation in order to provide potential possibilities for translation application in future clinical practice.

Innate Immune Cells during Machine Perfusion of Liver Grafts—The Janus Face of Hepatic Macrophages

“…Experimental data revealed that during the initial phase of IRI in cold ischemia, NK cells significantly increased in the liver parenchyma but did not participate in tissue damage. During the following warm IRI, NK cell activation by NKG2D, along with increased inflammatory cytokines such as TNF-alpha, IL1, and IL6, was observed [58]. On the other hand, there was an upregulation of the TRAIL ligand in NK cells after IRI, which led to decreased neutrophil infiltration, IL6, and transaminase level, suggesting that NK cells play a role in immune tolerance after transplantation [79].…”

“…DCs interact with T, NK, and NKT cells, while the latter might be correlated with IL10 and TGF-beta expression in an immunoreg- Distributed mainly in the perivenular and portal space, DCs are leukocytes that link innate and adaptive immune responses [57]. DCs interact with T, NK, and NKT cells, while the latter might be correlated with IL10 and TGF-beta expression in an immunoregulatory way [58]. Hepatic NK and NKT cells represent the predominant lymphocyte population.…”

“…In contrast to other lymphocyte populations such as B and T cells, NK and NKT cell activation is not due to the stimulation of one or two main receptors but is regulated by an ensemble of activating and inhibiting signals [78]. In hepatic IRI, receptors that are primarily engaged in NK cell activation are known to be NK granule 7; CD16; CD226; NKG2D; and NKp46, -44, and -30, while the killer cell immunoglobulin receptor (KIR), Ly49 receptor in mice, CD96, T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and lymphocyte activation gene 3 (LAG3) are described as being inhibitory receptors [58].…”

The Role of the NLRP3 Inflammasome and Programmed Cell Death in Acute Liver Injury

“…Therefore, in order to provide a clinical solution to this problem, it is important to deeply investigate the pathogenesis of LIRI. LIRI can be divided into two phases, ischemia and reperfusion, which are characterized by hypoxia-induced cell injury in the ischemic phase and immunoinflammation after the restoration of blood flow [ 133 ]. During ischemia, ROS production as well as organelle damage, are induced by glycogen depletion, inadequate oxygen supply, and ATP depletion, which can lead to hepatocyte injury and death [ 134 , 135 ].…”

Green Alternatives in Treatment of Liver Diseases: the Challenges of Traditional Medicine and Green Nanomedicine

“…The liver is the center of numerous physiological processes, including nutrient metabolism, immune system support, lipid and cholesterol homeostasis, and the breakdown of xenobiotic compounds; [1] due to its multiple functions, the liver is in contact with exogenous and systemic substances continuously and is therefore highly exposed to injury and possible develop-ment of acute and/or chronic diseases. [2,3] The main damaging factors of the liver are viruses, high alcohol and drug consumption, an unbalanced diet, and metabolic and autoimmune diseases. Indeed, liver diseases constitute a major health problem, as they endanger human life; [4] these etiologies, together or individually, can trigger a cascade of liver diseases, from simple cellular damage to cirrhosis and even liver cancer.…”