The Role of Complement in Liver Injury, Regeneration, and Transplantation

Abstract

The liver is both an immunologically complex and a privileged organ. The innate immune system is a central player, in which the complement system emerges as a pivotal part of liver homeostasis, immune responses, and crosstalk with other effector systems in both innate and adaptive immunity. The liver produces the majority of the complement proteins and is the home of important immune cells such as Kupffer cells. Liver immune responses are delicately tuned between tolerance to many antigens flowing in from the alimentary tract, a tolerance that likely makes the liver less prone to rejection than other solid organ transplants, and reaction to local injury, systemic inflammation, and regeneration. Notably, complement is a double-edged sword as activation is detrimental by inducing inflammatory tissue damage in, for example, ischemia-reperfusion injury and transplant rejection yet is beneficial for liver tissue regeneration. Therapeutic complement inhibition is rapidly developing for routine clinical treatment of several diseases. In the liver, targeted inhibition of damaged tissue may be a rational and promising approach to avoid further tissue destruction and simultaneously preserve beneficial effects of complement in areas of proliferation. Here, we argue that complement is a key system to manipulate in the liver in several clinical settings, including liver injury and regeneration after major surgery and preservation of the organ during transplantation.

Figure 1

The complement system. The complement system can be activated through three pathways (top), which converge on C3 to activate the common terminal pathway. Several pattern recognition receptors, like C1q, ficolins, mannose binding lectin, and collectins, activate the system after binding to exogenous PAMPs and DAMPs. The alternative pathway has another important function in the complement system, providing an amplification loop that enhances C3 activation independently of which pathway is initially activated. Activation of C3 leads to formation of a C5 convertase, which cleaves C5 into C5a and C5b. The anaphylatoxins C3a and C5a bind to their receptors, initiating downstream production of mediators, leading to inflammation. C5b initiates the formation of C5b‐9, often called the TCC, which forms the MAC if inserted into a membrane or sC5b‐9 is released to the fluid phase. The MAC may lead to lysis of bacteria and cells or, if sublytic, to activation of cells, whereas sC5b‐9 is a useful plasma marker of complement activation. The complement system is tightly regulated by soluble inhibitors including the important factor H controlling the alternative pathway. Abbreviations: AB, antibody; Ag, antigen; B, factor B; CRP, C‐reactive protein; H, factor H; MASP, mannose‐associated serine protease; MBL, mannose binding lectin; P, factor P.

Figure 2

The complement system and crosstalk with other innate immune effector systems in liver IRI, regeneration, and transplantation. The complement system is activated by endogenously derived DAMPs in IRI, regeneration, and transplantation. The activation products from the complement cascade activate cells by binding to cell receptors, which frequently crosstalk with receptors and mediators of a number of effector molecules and mechanisms downstream in the innate and adaptive immune system. The most important complement effector molecules are C3a, C5a, and C5b‐9. C4d is a split product of the classical and lectin pathway activation and is covalently bound to cell membranes. If immunohistopathological staining in liver biopsies from liver grafts shows binding of C4d, AMR is suspected. Complement activates other effector systems, which frequently crosstalk and activate complement, consistent with a widespread bilateral and multilateral crosstalk between the complement system and these other effector systems. In particular, abundant crosstalk occurs with the hemostatic system (“thromboinflammation”) including the other plasma cascades and the platelets. Complement activation promotes hemostasis by several routes; C5a activation of C5aR1 on monocytes and endothelial cells induces up‐regulation of tissue factor (not shown) and thereby promotes coagulation through the extrinsic pathway. C3a binding to C3aR on platelets primes the cell for activation and insertion of MAC through the platelet membrane, promoting release of prothrombotic platelet microvesicles. Furthermore, there is an extensive crosstalk between complement and granulocytes, releasing enzymes like matrix metalloproteinases, and reactive oxygen species. Finally, there are advanced crosslinks between complement and the TLRs, producing a range of proinflammatory and anti‐inflammatory cytokines, and with the inflammasome. This crosstalk may lead to a synergistic effect on the effector mechanisms involved and thereby produce a stronger inflammatory response. The main cellular players in these mechanisms, except for hepatocytes, are granulocytes, endothelial cells, platelets, dendritic cells, monocytes, and macrophages/Kupffer cells. Although there is much overlap with respect to the complement‐induced activation of the different cells, granulocytes typically produce and release proteases and ROS; endothelial cells express adhesion molecules; and macrophages/Kupffer cells, monocytes, and dendritic cells typically up‐regulate TLRs and their coreceptor CD14, produce and release cytokines, and assemble and activates the inflammasome. Platelets are increasingly recognized as important immune cells and can display or release all of the effector molecules shown, in particular dependent on the C5b‐9 insertion. Abbreviations: MMP, matrix metalloproteinase; ROS, reactive oxygen species. Printed with permission from Kari C. Toverud.

Figure 3

Liver IRI, regeneration, and transplantation. The figure represents an overview of the text’s three main topics. Liver IRI exemplified by hilar clamping (“Pringle maneuver”), regeneration exemplified after liver surgery, and transplantation exemplified by a segment 2 to 3 allograft (the “Resection And Partial Liver Segment 2/3 Transplantation With Delayed Total Hepatectomy [RAPID] concept”). Printed with permission from Kari C. Toverud.