The complement cascade as a mediator of tissue growth and regeneration

Abstract

Recent evidence has demonstrated that the complement cascade is involved in a variety of physiologic and pathophysiologic processes in addition to its role as an immune effector. Research in a variety of organ systems has shown that complement proteins are direct participants in maintenance of cellular turnover, healing, proliferation and regeneration. As a physiologic housekeeper, complement proteins maintain tissue integrity in the absence of inflammation by disposing of cellular debris and waste, a process critical to the prevention of autoimmune disease. Developmentally, complement proteins influence pathways including hematopoietic stem cell engraftment, bone growth, and angiogenesis. They also provide a potent stimulus for cellular proliferation including regeneration of the limb and eye in animal models, and liver proliferation following injury. Here, we describe the complement cascade as a mediator of tissue growth and regeneration.

Fig. 1

The complement cascade is comprised of the Classical, Alternative, and Mannose Binding Lectin pathways. Although the activation and amplification of each pathway is unique, they all converge with cleavage of C3 into its main split products, C3a and C3b, ultimately resulting in formation of the membrane attack complex (MAC). Historically considered a critical arm of innate immunity, emerging research has implicated various complement proteins in proliferative and regenerative processes in organs including bone, marrow, liver, and connective tissues. C1q maintains appropriate turnover and clearance of cellular debris, while C4 maintains B cell tolerance, processes critical in the prevention of autoimmune disease. Hematopoietic stem cell homing, chemotaxis, engraftment, and mobilization are heavily influenced by the anaphylatoxins C3a and C5a. Additionally, they help facilitate hepatocyte protection and regeneration in mouse models of toxic and surgical injury. Limb and lens regeneration in urodele amphibians are mediated by C3 and C5, while complement proteins such as C1s, C5, C9, factor B and properdin are distributed throughout immature, developing bone and appear to be important in osteogenesis. MBL mannose-binding lectin, MASP mannose-binding lectin associated serine proteases, HSC hematopoietic stem cell