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Inflammation Research
Published in: Inflammation Research 11/2010

Open Access 01-11-2010 | Review

The complement cascade as a mediator of tissue growth and regeneration

Authors: Martin J. Rutkowski, Michael E. Sughrue, Ari J. Kane, Brian J. Ahn, Shanna Fang, Andrew T. Parsa

Published in: Inflammation Research | Issue 11/2010

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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.
Literature
1.
Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science. 1996;271:348–50.CrossRefPubMed
2.
Cole DS, Morgan BP. Beyond lysis: how complement influences cell fate. Clin Sci (Lond). 2003;104:455–66.CrossRef
3.
4.
Kemper C, Atkinson JP. T-cell regulation: with complements from innate immunity. Nat Rev Immunol. 2007;7:9–18.CrossRefPubMed
5.
Thomas A, Gasque P, Vaudry D, Gonzalez B, Fontaine M. Expression of a complete and functional complement system by human neuronal cells in vitro. Int Immunol. 2000;12:1015–23.CrossRefPubMed
6.
7.
Mastellos D, Lambris JD. Complement: more than a ‘guard’ against invading pathogens? Trends Immunol. 2002;23:485–91.CrossRefPubMed
8.
D’Ambrosio AL, Pinsky DJ, Connolly ES. The role of the complement cascade in ischemia/reperfusion injury: implications for neuroprotection. Mol Med. 2001;7:367–82.PubMed
9.
Markiewski MM, Lambris JD. The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am J Pathol. 2007;171:715–27.CrossRefPubMed
10.
Rose KL, Paixao-Cavalcante D, Fish J, Manderson AP, Malik TH, Bygrave AE, et al. Factor I is required for the development of membranoproliferative glomerulonephritis in factor H-deficient mice. J Clin Invest. 2008;118:608–18.PubMed
11.
Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Walport MJ, et al. Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet. 2002;31:424–8.PubMed
12.
Pickering MC, Warren J, Rose KL, Carlucci F, Wang Y, Walport MJ, et al. Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice. Proc Natl Acad Sci USA. 2006;103:9649–54.CrossRefPubMed
13.
Manderson AP, Botto M, Walport MJ. The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol. 2004;22:431–56.CrossRefPubMed
14.
Wouters D, Voskuyl AE, Molenaar ET, Dijkmans BA, Hack CE. Evaluation of classical complement pathway activation in rheumatoid arthritis: measurement of C1q–C4 complexes as novel activation products. Arthritis Rheum. 2006;54:1143–50.CrossRefPubMed
15.
Storch MK, Piddlesden S, Haltia M, Iivanainen M, Morgan P, Lassmann H. Multiple sclerosis: in situ evidence for antibody- and complement-mediated demyelination. Ann Neurol. 1998;43:465–71.CrossRefPubMed
16.
Botto M, Dell’Agnola C, Bygrave AE, Thompson EM, Cook HT, Petry F, et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet. 1998;19:56–9.CrossRefPubMed
17.
Gaipl US, Beyer TD, Heyder P, Kuenkele S, Bottcher A, Voll RE, et al. Cooperation between C1q and DNase I in the clearance of necrotic cell-derived chromatin. Arthritis Rheum. 2004;50:640–9.CrossRefPubMed
18.
Korb LC, Ahearn JM. C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited. J Immunol. 1997;158:4525–8.PubMed
19.
Mitchell DA, Pickering MC, Warren J, Fossati-Jimack L, Cortes-Hernandez J, Cook HT, et al. C1q deficiency and autoimmunity: the effects of genetic background on disease expression. J Immunol. 2002;168:2538–43.PubMed
20.
Taylor PR, Carugati A, Fadok VA, Cook HT, Andrews M, Carroll MC, et al. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med. 2000;192:359–66.CrossRefPubMed
21.
Muller-Eberhard HJ. Molecular organization and function of the complement system. Annu Rev Biochem. 1988;57:321–47.CrossRefPubMed
22.
Manderson AP, Pickering MC, Botto M, Walport MJ, Parish CR. Continual low-level activation of the classical complement pathway. J Exp Med. 2001;194:747–56.CrossRefPubMed
23.
Ferry H, Potter PK, Crockford TL, Nijnik A, Ehrenstein MR, Walport MJ, et al. Increased positive selection of B1 cells and reduced B cell tolerance to intracellular antigens in c1q-deficient mice. J Immunol. 2007;178:2916–22.PubMed
24.
Ferry H, Jones M, Vaux DJ, Roberts IS, Cornall RJ. The cellular location of self-antigen determines the positive and negative selection of autoreactive B cells. J Exp Med. 2003;198:1415–25.CrossRefPubMed
25.
Chen Z, Koralov SB, Kelsoe G. Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. J Exp Med. 2000;192:1339–52.CrossRefPubMed
26.
Prodeus AP, Goerg S, Shen LM, Pozdnyakova OO, Chu L, Alicot EM, et al. A critical role for complement in maintenance of self-tolerance. Immunity. 1998;9:721–31.CrossRefPubMed
27.
Strainic MG, Liu J, Huang D, An F, Lalli PN, Muqim N, et al. Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity. 2008;28:425–35.CrossRefPubMed
28.
Lalli PN, Strainic MG, Yang M, Lin F, Medof ME, Heeger PS. Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis. Blood. 2008;112:1759–66.CrossRefPubMed
29.
Chen A, Gaddipati S, Hong Y, Volkman DJ, Peerschke EI, Ghebrehiwet B. Human T cells express specific binding sites for C1q. Role in T cell activation and proliferation. J Immunol. 1994;153:1430–40.PubMed
30.
Molina H, Miwa T, Zhou L, Hilliard B, Mastellos D, Maldonado MA, et al. Complement-mediated clearance of erythrocytes: mechanism and delineation of the regulatory roles of Crry and DAF. Decay-accelerating factor. Blood. 2002;100:4544–9.CrossRefPubMed
31.
Sun X, Funk CD, Deng C, Sahu A, Lambris JD, Song WC. Role of decay-accelerating factor in regulating complement activation on the erythrocyte surface as revealed by gene targeting. Proc Natl Acad Sci USA. 1999;96:628–33.CrossRefPubMed
32.
Scolding NJ, Morgan BP, Houston WA, Linington C, Campbell AK, Compston DA. Vesicular removal by oligodendrocytes of membrane attack complexes formed by activated complement. Nature. 1989;339:620–2.CrossRefPubMed
33.
Lee H, Ratajczak MZ. Innate immunity: a key player in the mobilization of hematopoietic stem/progenitor cells. Arch Immunol Ther Exp (Warsz). 2009;57:269–78.CrossRef
34.
Reca R, Mastellos D, Majka M, Marquez L, Ratajczak J, Franchini S, et al. Functional receptor for C3a anaphylatoxin is expressed by normal hematopoietic stem/progenitor cells, and C3a enhances their homing-related responses to SDF-1. Blood. 2003;101:3784–93.CrossRefPubMed
35.
Ratajczak J, Reca R, Kucia M, Majka M, Allendorf DJ, Baran JT, et al. Mobilization studies in mice deficient in either C3 or C3a receptor (C3aR) reveal a novel role for complement in retention of hematopoietic stem/progenitor cells in bone marrow. Blood. 2004;103:2071–8.CrossRefPubMed
36.
Ratajczak MZ, Reca R, Wysoczynski M, Kucia M, Baran JT, Allendorf DJ, et al. Transplantation studies in C3-deficient animals reveal a novel role of the third complement component (C3) in engraftment of bone marrow cells. Leukemia. 2004;18:1482–90.CrossRefPubMed
37.
Honczarenko M, Ratajczak MZ, Nicholson-Weller A, Silberstein LE. Complement C3a enhances CXCL12 (SDF-1)-mediated chemotaxis of bone marrow hematopoietic cells independently of C3a receptor. J Immunol. 2005;175:3698–706.PubMed
38.
Wysoczynski M, Reca R, Lee H, Wu W, Ratajczak J, Ratajczak MZ. Defective engraftment of C3aR−/− hematopoietic stem progenitor cells shows a novel role of the C3a–C3aR axis in bone marrow homing. Leukemia. 2009;23:1455–61.CrossRefPubMed
39.
Reca R, Cramer D, Yan J, Laughlin MJ, Janowska-Wieczorek A, Ratajczak J, et al. A novel role of complement in mobilization: immunodeficient mice are poor granulocyte-colony stimulating factor mobilizers because they lack complement-activating immunoglobulins. Stem Cells. 2007;25:3093–100.CrossRefPubMed
40.
Lee HM, Wu W, Wysoczynski M, Liu R, Zuba-Surma EK, Kucia M, et al. Impaired mobilization of hematopoietic stem/progenitor cells in C5-deficient mice supports the pivotal involvement of innate immunity in this process and reveals novel promobilization effects of granulocytes. Leukemia. 2009;23:2052–62.CrossRefPubMed
41.
Nepomuceno RR, Tenner AJ. C1qRP, the C1q receptor that enhances phagocytosis, is detected specifically in human cells of myeloid lineage, endothelial cells, and platelets. J Immunol. 1998;160:1929–35.PubMed
42.
Petrenko O, Beavis A, Klaine M, Kittappa R, Godin I, Lemischka IR. The molecular characterization of the fetal stem cell marker AA4. Immunity. 1999;10:691–700.CrossRefPubMed
43.
Andrades JA, Nimni ME, Becerra J, Eisenstein R, Davis M, Sorgente N. Complement proteins are present in developing endochondral bone and may mediate cartilage cell death and vascularization. Exp Cell Res. 1996;227:208–13.CrossRefPubMed
44.
Sakiyama H, Inaba N, Toyoguchi T, Okada Y, Matsumoto M, Moriya H, et al. Immunolocalization of complement C1s and matrix metalloproteinase 9 (92 kDa gelatinase/type IV collagenase) in the primary ossification center of the human femur. Cell Tissue Res. 1994;277:239–45.PubMed
45.
Nakagawa K, Sakiyama H, Fukazawa T, Matsumoto M, Takigawa M, Toyoguchi T, et al. Coordinated change between complement C1s production and chondrocyte differentiation in vitro. Cell Tissue Res. 1997;289:299–305.CrossRefPubMed
46.
Toyoguchi T, Yamaguchi K, Nakagawa K, Fukusawa T, Moriya H, Sakiyama H. Change of complement C1s synthesis during development of hamster cartilage. Cell Tissue Res. 1996;285:199–204.CrossRefPubMed
47.
Sato T, Hong MH, Jin CH, Ishimi Y, Udagawa N, Shinki T, et al. The specific production of the third component of complement by osteoblastic cells treated with 1 alpha, 25-dihydroxyvitamin D3. FEBS Lett. 1991;285:21–4.CrossRefPubMed
48.
Hong MH, Jin CH, Sato T, Ishimi Y, Abe E, Suda T. Transcriptional regulation of the production of the third component of complement (C3) by 1 alpha, 25-dihydroxyvitamin D3 in mouse marrow-derived stromal cells (ST2) and primary osteoblastic cells. Endocrinology. 1991;129:2774–9.CrossRefPubMed
49.
Jin CH, Shinki T, Hong MH, Sato T, Yamaguchi A, Ikeda T, et al. 1 alpha, 25-dihydroxyvitamin D3 regulates in vivo production of the third component of complement (C3) in bone. Endocrinology. 1992;131:2468–75.CrossRefPubMed
50.
Sato T, Abe E, Jin CH, Hong MH, Katagiri T, Kinoshita T, et al. The biological roles of the third component of complement in osteoclast formation. Endocrinology. 1993;133:397–404.CrossRefPubMed
51.
Kimura Y, Madhavan M, Call MK, Santiago W, Tsonis PA, Lambris JD, et al. Expression of complement 3 and complement 5 in newt limb and lens regeneration. J Immunol. 2003;170:2331–9.PubMed
52.
Del Rio-Tsonis K, Tsonis PA, Zarkadis IK, Tsagas AG, Lambris JD. Expression of the third component of complement, C3, in regenerating limb blastema cells of urodeles. J Immunol. 1998;161:6819–24.PubMed
53.
Legoedec J, Gasque P, Jeanne JF, Fontaine M. Expression of the complement alternative pathway by human myoblasts in vitro: biosynthesis of C3, factor B, factor H and factor I. Eur J Immunol. 1995;25:3460–6.CrossRefPubMed
54.
Legoedec J, Gasque P, Jeanne JF, Scotte M, Fontaine M. Complement classical pathway expression by human skeletal myoblasts in vitro. Mol Immunol. 1997;34:735–41.CrossRefPubMed
55.
Mastellos D, Papadimitriou JC, Franchini S, Tsonis PA, Lambris JD. A novel role of complement: mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration. J Immunol. 2001;166:2479–86.PubMed
56.
57.
Puschel GP, Nolte A, Schieferdecker HL, Rothermel E, Gotze O, Jungermann K. Inhibition of anaphylatoxin C3a- and C5a- but not nerve stimulation- or Noradrenaline-dependent increase in glucose output and reduction of flow in Kupffer cell-depleted perfused rat livers. Hepatology. 1996;24:685–90.CrossRefPubMed
58.
Schieferdecker HL, Pestel S, Puschel GP, Gotze O, Jungermann K. Increase by anaphylatoxin C5a of glucose output in perfused rat liver via prostanoids derived from nonparenchymal cells: direct action of prostaglandins and indirect action of thromboxane A(2) on hepatocytes. Hepatology. 1999;30:454–61.CrossRefPubMed
59.
Schieferdecker HL, Schlaf G, Koleva M, Gotze O, Jungermann K. Induction of functional anaphylatoxin C5a receptors on hepatocytes by in vivo treatment of rats with IL-6. J Immunol. 2000;164:5453–8.PubMed
60.
Daveau M, Benard M, Scotte M, Schouft MT, Hiron M, Francois A, et al. Expression of a functional C5a receptor in regenerating hepatocytes and its involvement in a proliferative signaling pathway in rat. J Immunol. 2004;173:3418–24.PubMed
61.
Markiewski MM, Mastellos D, Tudoran R, De Angelis RA, Strey CW, Franchini S, et al. C3a and C3b activation products of the third component of complement (C3) are critical for normal liver recovery after toxic injury. J Immunol. 2004;173:747–54.PubMed
62.
Strey CW, Markiewski M, Mastellos D, Tudoran R, Spruce LA, Greenbaum LE, et al. The proinflammatory mediators C3a and C5a are essential for liver regeneration. J Exp Med. 2003;198:913–23.CrossRefPubMed
63.
Markiewski MM, De Angelis RA, Strey CW, Foukas PG, Gerard C, Gerard N, et al. The regulation of liver cell survival by complement. J Immunol. 2009;182:5412–8.CrossRefPubMed
64.
Hong F, Nguyen VA, Shen X, Kunos G, Gao B. Rapid activation of protein kinase B/Akt has a key role in antiapoptotic signaling during liver regeneration. Biochem Biophys Res Commun. 2000;279:974–9.CrossRefPubMed
65.
Corradetti MN, Guan KL. Upstream of the mammalian target of rapamycin: do all roads pass through mTOR? Oncogene. 2006;25:6347–60.CrossRefPubMed
Metadata
Title
The complement cascade as a mediator of tissue growth and regeneration
Authors
Martin J. Rutkowski
Michael E. Sughrue
Ari J. Kane
Brian J. Ahn
Shanna Fang
Andrew T. Parsa
Publication date
01-11-2010
Publisher
SP Birkhäuser Verlag Basel
Published in
Inflammation Research / Issue 11/2010
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-010-0220-6

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