Abstract
The complement system is a major component of innate immunity and has been commonly identified as a central element in host defense, clearance of immune complexes, and tissue homeostasis. After ischemia-reperfusion injury (IRI), the complement system is activated by endogenous ligands that trigger proteolytic cleavage of complement components via the classical, lectin and/or alternative pathway. The result is the formation of terminal complement components C3a, C5a, and the membrane attack complex (C5b-9 or MAC), all of which play pivotal roles in the amplification of the inflammatory response, chemotaxis, neutrophil/monocyte recruitment and activation, and direct tubular cell injury. However, recent evidence suggests that complement activity transcends innate host defense and there is increasing data suggesting complement as a regulator in processes such as allo-immunity, stem cell differentiation, tissue repair, and progression to fibrosis. In this review, we discuss recent advances addressing the role of complement as a regulator of IRI and renal fibrosis after organ donation for transplantation. We will also briefly discuss currently approved therapies that target complement activity in kidney ischemia-reperfusion and transplantation.
Highlights
The complement system is a major component of innate immunity and has been commonly identified as a central element in host defense, clearance of immune complexes, and tissue homeostasis
In addition to the proteins involved in cleavage and activation of the complement cascade, the complement system is composed of a series of soluble (C4BP, Factor H, and C1 inhibitor (C1-INH)) and membrane-bound (CD35, CD46, CD55, and CD59) regulatory proteins that prevent excessive activation and consumption of complement components [3]
Animals lacking MASP2 are protected from injury following both myocardial and intestinal ischemic injury and a report by van der Pol in a rat model of renal ischemia-reperfusion injury (IRI) suggests a novel role for mannose-binding lectin (MBL) in cellular injury independent of complement activation in which internalization of circulating MBL resulted in direct tubular necrosis [22,23]
Summary
The multiple interactions between injury, immune response, and tissue repair are still a matter of intense study. Recent research indicates a role for complement in the regulation of tissue repair and the progression of fibrosis in models of acute kidney injury. These findings place the complement system as a centerpiece target in the elucidation of the precise mechanisms governing adequate (adaptive) and abnormal (maladaptive) tissue repair. The development of targeted treatment strategies that lessen the need for immunosuppression of transplant recipients and that have the ability to reduce inflammatory injury and tissue fibrosis is of paramount importance to maximize the limited organ donor pool and improve current transplant outcomes worldwide. Authors' contributions JSD, AJ, and LAF developed the review concept.
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