Liver ischaemia–reperfusion injury: a new understanding of the role of innate immunity

• Published in: Nature reviews. Gastroenterology & hepatology Vol. 19; no. 4; pp. 239 - 256
• Main Authors: Hirao, Hirofumi, Nakamura, Kojiro, Kupiec-Weglinski, Jerzy W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2022; Nature Publishing Group
• Subjects: 692/698/2741/288; 692/700/565/545/576/402; Biomedicine; Endothelial Cells; Gastroenterology; Graft rejection; Hepatocytes; Hepatology; Humans; Immunity, Innate; Immunomodulation; Inflammation; Innate immunity; Ischemia; Kupffer cells; Leukocyte migration; Leukocytes (neutrophilic); Liver; Liver diseases; Liver transplantation; Macrophages; Medical innovations; Medicine; Medicine & Public Health; Monocytes; Neutrophils; Platelets; Reperfusion; Reperfusion Injury; Review Article; Risk factors; Transplants & implants
• ISSN: 1759-5045; 1759-5053
• DOI: 10.1038/s41575-021-00549-8

Liver ischaemia–reperfusion injury (LIRI), a local sterile inflammatory response driven by innate immunity, is one of the primary causes of early organ dysfunction and failure after liver transplantation. Cellular damage resulting from LIRI is an important risk factor not only for graft dysfunction but also for acute and even chronic rejection and exacerbates the shortage of donor organs for life-saving liver transplantation. Hepatocytes, liver sinusoidal endothelial cells and Kupffer cells, along with extrahepatic monocyte-derived macrophages, neutrophils and platelets, are all involved in LIRI. However, the mechanisms underlying the responses of these cells in the acute phase of LIRI and how these responses are orchestrated to control and resolve inflammation and achieve homeostatic tissue repair are not well understood. Technological advances allow the tracking of cells to better appreciate the role of hepatic macrophages and platelets (such as their origin and immunomodulatory and tissue-remodelling functions) and hepatic neutrophils (such as their selective recruitment, anti-inflammatory and tissue-repairing functions, and formation of extracellular traps and reverse migration) in LIRI. In this Review, we summarize the role of macrophages, platelets and neutrophils in LIRI, highlight unanswered questions, and discuss prospects for innovative therapeutic regimens against LIRI in transplant recipients. In this Review, Kupiec-Weglinski and colleagues describe the roles of macrophages, neutrophils, and platelets in liver ischaemia–reperfusion injury (LIRI) and discuss potential therapeutic strategies for treating LIRI in transplant recipients. Key points Novel therapies are needed to mitigate liver ischaemia–reperfusion injury (LIRI) in liver transplant recipients as it is an inevitable detrimental event following surgery that affects clinical outcomes and contributes to donor organ shortage. A mixture of cell death pathways — apoptosis, necrosis, necroptosis, pyroptosis and ferroptosis — facilitate LIRI-triggered hepatocellular damage, each of which, except apoptosis, provokes an inflammatory immune cascade in the stressed liver. In both the acute and resolution phase of LIRI, macrophages, neutrophils and platelets communicate, regulate one another and have competing and/or opposing roles in the resulting pathogenesis. During LIRI, neutrophils not only elicit local inflammation but reversely transmigrate into the circulation and, in coordination with platelets, promote distal organ injury by neutrophil extracellular trap-associated thrombosis. Macrophage reprogramming at the LIRI site — phagocytosis via efferocytosis and bi-directional crosstalk with neutrophils — is crucial for the resolution of inflammation and eventual return to homeostasis. Novel macrophage and neutrophil-targeted therapeutic strategies imposing reparative phenotypes and inhibition of NETosis are now in preclinical development.