Abstract
The complement system plays a major role in innate immune defenses against infectious agents, but exaggerated activation of complement can lead to severe tissue injury. Systemic (intravascular) activation of complement can, via C5a, lead to neutrophil (PMN) activation, sequestration and adhesion to the pulmonary capillary endothelium, resulting in damage and necrosis of vascular endothelial cells and acute lung injury (ALI). Intrapulmonary (intraalveolar) activation of complement can cause ALI that is complement and PMN-dependent, resulting in a cytokine/chemokine storm that leads to intense ALI. Surprisingly, C3−/− mice develop the full intensity of ALI in a C5a-dependent manner due to the action of thrombin that generates C5a directly from C5. There is conflicting evidence on the role of the second C5a receptor, C5L2 in development of ALI. There is accumulating evidence that C5a may suppress inflammatory responses or divert them from Th1 to Th2 responses, impacting the innate immune system. Finally, in experimental polymicrobial sepsis, there is evidence that many of the adverse outcomes can be linked to the roles of C5a and engagement of its two receptors, C5aR and C5L2. These observations underscore the diversity of effects of C5a in a variety of inflammatory settings.
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Amara, U., Flierl, M.A., Rittirsch, D., Klos, A., Chen, H., Acker, B., Bruckner, U.B., Nilsson, B., Gebhard, F., Lambris, J.D., and Huber-Lang, M. (2010). Molecular intercommunication between the complement and coagulation systems. Journal of Immunology, 185, 5628-5636
Bamberg, C.E., Mackay, C.R., Lee, H., Zahra, D., Jackson, J., Lim, Y.S., Whitfeld, P.L., Craig, S., Corsini, E., Lu, B., Gerard, C., and Gerard, N.P. (2010). The C5a Receptor (C5aR) C5L2 Is a Modulator of C5aR-mediated Signal Transduction. Journal of Biological Chemistry, 285, 7633-7644
Barton, P.A., and Warren, J.S. (1993). Complement component C5 modulates the systemic tumor necrosis factor response in murine endotoxic shock. Infection & Immunity, 61, 1474-1481
Cain, S.A., and Monk, P.N. (2002). The orphan receptor C5L2 has high affinity binding sites for complement fragments C5a and C5a des-Arg(74). Journal of Biological Chemistry, 277, 7165-7169
Chen, N.J., Mirtsos, C., Suh, D., Lu, Y.C., Lin, W.J., McKerlie, C., Lee, T., Baribault, H., Tian, H., and Yeh, W.C. (2007). C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a. Nature, 446, 203-207
Collard, C.D., Lekowski, R., Jordan, J.E., Agah, A., and Stahl, G.L. (1999). Complement activation following oxidative stress. Molecular Immunology, 36, 941-948
Czermak, B.J., Sarma, V., Pierson, C.L., Warner, R.L., Huber-Lang, M., Bless, N.M., Schmal, H., Friedl, H.P., and Ward, P.A. (1999). Protective effects of C5a blockade in sepsis. Nature Medicine, 5, 788-792
Donnelly, S.C., Haslett, C., Reid, P.T., Grant, I.S., Wallace, W.A., Metz, C.N., Bruce, L.J., and Bucala, R. (1997). Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome. Nature Medicine, 3, 320-323
Flierl, M.A., Rittirsch, D., Nadeau, B.A., Day, D.E., Zetoune, F.S., Sarma, J.V., Huber-Lang, M.S., and Ward, P.A. (2008). Functions of the complement components C3 and C5 during sepsis. Faseb Journal, 22, 3483-3490
Gannon, D.E., Varani, J., Phan, S.H., Ward, J.H., Kaplan, J., Till, G.O., Simon, R.H., Ryan, U.S., and Ward, P.A. (1987). Source of iron in neutrophil-mediated killing of endothelial cells. Laboratory Investigation, 57, 37-44
Gao, H., Neff, T., and Ward, P.A. (2006). Regulation of lung inflammation in the model of IgG immune-complex injury. Annual Review Of Pathology, 1, 215-242
Gerard, N.P., and Gerard, C. (1991). The chemotactic receptor for human C5a anaphylatoxin. Nature, 349, 614-617
Gerard, N.P., Lu, B., Liu, P., Craig, S., Fujiwara, Y., Okinaga, S., and Gerard, C. (2005). An anti-inflammatory function for the complement anaphylatoxin C5a-binding protein, C5L2. Journal of Biological Chemistry, 280, 39677-39680
Hammerschmidt, D.E., Weaver, L.J., Hudson, L.D., Craddock, P.R., and Jacob, H.S. (1980). Association ofcomplement activation and elevated plasma-C5a with adult respiratory distress syndrome. Pathophysiological relevance and possible prognostic value. Lancet, 1, 947-949
Hawlisch, H., Belkaid, Y., Baelder, R., Hildeman, D., Gerard, C., and Kohl, J. (2005). C5a negatively regulates toll-like receptor 4-induced immune responses. Immunity, 22, 415-426
Huber-Lang, M., Sarma, J.V., Zetoune, F.S., Rittirsch, D., Neff, T.A., McGuire, S.R., Lambris, J.D., Warner, R.L., Flierl, M.A., Hoesel, L.M., Gebhard, F., Younger, J.G., Drouin, S.M., Wetsel, R.A., and Ward, P.A. (2006). Generation of C5a in the absence of C3: a new complement activation pathway. Nature Medicine, 12, 682-687
Huber-Lang, M.S., Riedeman, N.C., Sarma, J.V., Younkin, E.M., McGuire, S.R., Laudes, I.J., Lu, K.T., Guo, R.F., Neff, T.A., Padgaonkar, V.A., Lambris, J.D., Spruce, L., Mastellos, D., Zetoune, F.S., and Ward, P.A. (2002a). Protection of innate immunity by C5aR antagonist in septic mice. FASEB Journal, 16, 1567-1574
Huber-Lang, M.S., Sarma, J.V., McGuire, S.R., Lu, K.T., Guo, R.F., Padgaonkar, V.A., Younkin, E.M., Laudes, I.J., Riedemann, N.C., Younger, J.G., and Ward, P.A. (2001). Protective effects of anti-C5a peptide antibodies in experimental sepsis. FASEB Journal, 15, 568-570
Huber-Lang, M.S., Younkin, E.M., Sarma, J.V., McGuire, S.R., Lu, K.T., Guo, R.F., Padgaonkar, V.A., Curnutte, J.T., Erickson, R., and Ward, P.A. (2002b). Complement-induced impairment of innate immunity during sepsis. Journal of Immunology, 169, 3223-3231
Kalant, D., Cain, S.A., Maslowska, M., Sniderman, A.D., Cianflone, K., and Monk, P.N. (2003). The chemoattractant receptor-like protein C5L2 binds the C3a des-Arg(77)/acylation-stimulating protein. Journal of Biological Chemistry, 278, 11123-11129
Kalant, D., MacLaren, R., Cui, W., Samanta, R., Monk, P.N., Laporte, S.A., and Cianflone, K. (2005). C5L2 is a functional receptor for acylation-stimulating protein. Journal of Biological Chemistry, 280, 23936-23944
Karp, C.L., Grupe, A., Schadt, E., Ewart, S.L., Keane-Moore, M., Cuomo, P.J., x00F, hl, J., Wahl, L., Kuperman, D., Germer, S., Aud, D., Peltz, G., and Wills-Karp, M. (2000). Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nature Immunology, 1, 221-226
Kohl, J., Baelder, R., Lewkowich, I.P., Pandey, M.K., Hawlisch, H., Wang, L.H., Best, J., Herman, N.S., Sproles, A.A., Zwirner, J., Whitsett, J.A., Gerard, C., Sfyroera, G., Lambris, J.D., and Wills-Karp, M. (2006). A regulatory role for the C5a anaphylatoxin in, type 2 immunity in asthma. Journal of Clinical Investigation, 116, 783-796
Lajoie, S., Lewkowich, I.P., Suzuki, Y., Clark, J.R., Sproles, A.A., Dienger, K., Budelsky, A.L., and Wills-Karp, M. (2010). Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nature Immunology, 11, 928-935
Larsen, G.L., Mitchell, B.C., and Henson, P.M. (1981). The pulmonary response of C5 sufficient and deficient mice to immune complexes. American Review of Respiratory Disease, 123, 434-439
Laudes, I.J., Chu, J.C., Sikranth, S., Huber-Lang, M., Guo, R.F., Riedemann, N., Sarma, J.V., Schmaier,A.H., and Ward, P.A. (2002). Anti-C5a ameliorates coagulation/fibrinolytic protein changes in a rat model of sepsis. American Journal of Pathology, 160, 1867-1875
Lee, H., Whitfeld, P.L., and Mackay, C.R. (2008). Receptors for complement C5a. The importance of C5aR and the enigmatic role of C5L2. Immunology & Cell Biology, 86, 153-160
Li, S., Boackle, S.A., Holers, V.M., Lambris, J.D., and Blatteis, C.M. (2005). Complement component C5a is integral to the febrile response of mice to lipopolysaccharide. Neuroimmunomodulation, 12, 67-80
Lotze, M.T., and Tracey, K.J. (2005). High-mobility group box 1 protein (HMGB): Nuclear weapon in the immune arsenal. Nature Reviews Immunology, 5, 331-342
Makita, H., Nishimura, M., Miyamoto, K., Nakano, T., Tanino, Y., Hirokawa, J., Nishihira, J., and Kawakami, Y. (1998). Effect of anti-macrophage migration inhibitory factor antibody on lipopolysaccharide-induced pulmonary neutrophil accumulation. American Journal of Respiratory & Critical Care Medicine, 158, 573-579
Markiewski, M.M., Nilsson, B., Ekdahl, K.N., Mollnes, T.E., and Lambris, J.D. (2007). Complement and coagulation: strangers or partners in crime? Trends in Immunology, 28, 184-192
Mulligan, M.S., Schmid, E., Beck-Schimmer, B., Till, G.O., Friedl, H.P., Brauer, R.B., Hugli, T.E., Miyasaka, M., Warner, R.L., Johnson, K.J., and Ward, P.A. (1996). Requirement and role of C5a in acute lung inflammatory injury in rats. Journal of Clinical Investigation, 98, 503-512
Niederbichler, A.D., Hoesel, L.M., Westfall, M.V., Gao, H.W., Ipaktchi, K.R., Sun, L., Zetoune, F.S., Su, G.L., Arbabi, S., Sarma, J.V., Wang, S.C., Hemmila, M.R., and Ward, P.A. (2006). An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction. Journal of Experimental Medicine, 203, 53-61
Nishihira, J. (2000). Macrophage migration inhibitory factor (MIF): its essential role in the immune system and cell growth. Journal of Interferon & Cytokine Research, 20, 751-762
Okinaga, S., Slattery, D., Humbles, A., Zsengeller, Z., Morteau, O., Kinrade, M.B., Brodbeck, R.M., Krause, J.E., Choe, H.R., Gerard, N.P., and Gerard, C. (2003). C5L2, a nonsignaling C5A binding protein. Biochemistry, 42, 9406-9415
Pittet, J.F., Mackersie, R.C., Martin, T.R., and Matthay, M.A. (1997). Biological markers of acute lung injury: prognostic and pathogenetic significance. American Journal of Respiratory & Critical Care Medicine, 155, 1187-1205
Prodeus, A.P., Zhou, X.N., Maurer, M., Galli, S.J., and Carroll, M.C. (1997). Impaired mast cell-dependent natural immunity in complement C3-deficient mice. Nature, 390, 172-175
Qin, S.X., Wang, H.C., Yuan, R.Q., Li, H., Ochani, M., Ochani, K., Rosas-Ballina, M., Czura, C.J., Huston, J.M., Miller, E., Lin, X.C., Sherry, B., Kumar, A., LaRosa, G., Newman, W., Tracey, K.J., and Yang, H. (2006). Role of HMGB1 in apoptosis-mediated sepsis lethality. Journal of Experimental Medicine, 203, 1637-1642
Ravetch, J.V., and Clynes, R.A. (1998). Divergent roles for Fc receptors and complement in vivo. Annual Review of Immunology, 16, 421-432
Riedemann, N.C., Guo, R.F., Laudes, I.J., Keller, K., Sarma, V.J., Padgaonkar, V., Zetoune, F.S., and Ward, P.A. (2002). C5a receptor and thymocyte apoptosis in sepsis. FASEB Journal, 16, 887-888
Rittirsch, D., Flierl, M.A., Day, D.E., Nadeau, B.A., McGuire, S.R., Hoesel, L.M., Ipaktchi, K., Zetoune, F.S., Sarma, J.V., Leng, L., Huber-Lang, M.S., Neff, T.A., Bucala, R., and Ward, P.A. (2008a). Acute lung injury induced by lipopolysaccharide is independent of complement activation. Journal of Immunology, 180, 7664-7672
Rittirsch, D., Flierl, M.A., Nadeau, B.A., Day, D.E., Huber-Lang, M., Mackay, C.R., Zetoune, F.S., Gerard, N.P., Cianflone, K., Kohl, J., Gerard, C., Sarma, J.V., and Ward, P.A. (2008b). Functional roles for C5a receptors in sepsis. Nature Medicine, 14, 551-557
Scola, A.M., Johswich, K.O., Morgan, B.P., Klos, A., and Monk, P.N. (2009). The human complement fragment receptor, C5L2, is a recycling decoy receptor. Molecular Immunology, 46, 1149-1162
Seekamp, A., Mulligan, M.S., Till, G.O., and Ward, P.A. (1993). Requirements for neutrophil products and L-arginine in ischemia-reperfusion injury. American Journal of Pathology, 142, 1217-1226
Seekamp, A., and Ward, P.A. (1993). Ischemia-reperfusion injury. Agents & Actions - Supplements, 41, 137-152
Solomkin, J.S., Cotta, L.A., Satoh, P.S., Hurst, J.M., and Nelson, R.D. (1985). Complement activation and clearance in acute illness and injury: evidence for C5a as a cell-directed mediator of the adult respiratory distress syndrome in man. Surgery, 97, 668-678
Sylvestre, D., Clynes, R., Ma, M., Warren, H., Carroll, M.C., and Ravetch, J.V. (1996). Immunoglobulin G-mediated inflammatory responses develop normally in complement-deficient mice. Journal of Experimental Medicine, 184, 2385-2392
Till, G.O., Friedl, H.P., and Ward, P.A. (1991). Lung injury and complement activation: role of neutrophils and xanthine oxidase. Free Radical Biology & Medicine, 10, 379-386
Till, G.O., Johnson, K.J., Kunkel, R., and Ward, P.A. (1982). Intravascular activation of complement and acute lung injury. Dependency on neutrophils and toxic oxygen metabolites. Journal of Clinical Investigation, 69, 1126-1135
Till, G.O., Morganroth, M.L., Kunkel, R., and Ward, P.A. (1987). Activation of C5 by cobra venom factor is required in neutrophil-mediated lung injury in the rat. American Journal of Pathology, 129, 44-53
Varani, J., Fligiel, S.E., Till, G.O., Kunkel, R.G., Ryan, U.S., and Ward, P.A. (1985). Pulmonary endothelial cell killing by human neutrophils. Possible involvement of hydroxyl radical. Laboratory Investigation, 53, 656-663
Ward, P.A. (1996). Rous-Whipple Award Lecture. Role of complement in lung inflammatory injury. American Journal of Pathology, 149, 1081-1086
Ward, P.A. (2010). The Harmful Role of C5a on Innate Immunity in Sepsis. Journal of Innate Immunity, 2, 439-445
Ward, P.A., and Hill, J.H. (1970). C5 chemotactic fragments produced by an enzyme in lysosomal granules of neutrophils. Journal of Immunology, 104, 535-543
Warren, J.S., Yabroff, K.R., Remick, D.G., Kunkel, S.L., Chensue, S.W., Kunkel, R.G., Johnson, K.J., and Ward, P.A. (1989). Tumor necrosis factor participates in the pathogenesis of acute immune complex alveolitis in the rat. Journal of Clinical Investigation, 84, 1873-1882
Watford, W.T., Ghio, A.J., and Wright, J.R. (2000). Complement-mediated host defense in the lung. American Journal of Physiology - Lung Cellular & Molecular Physiology, 279, L790-798
Watford, W.T., Wright, J.R., Hester, C.G., Jiang, H., and Frank, M.M. (2001). Surfactant protein A regulates complement activation. Journal of Immunology, 167, 6593-6600
Zhang, X., Kimura, Y., Fang, C., Zhou, L., Sfyroera, G., Lambris, J.D., Wetsel, R.A., Miwa, T., and Song, W.-C. (2007). Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood, 110, 228-236
Zhang, X., Schmudde, I., Laumonnier, Y., Pandey, M.K., Clark, J.R., Konig, P., Gerard, N.P., Gerard, C., Wills-Karp, M., and Kohl, J. (2010). A Critical Role for C5L2 in the Pathogenesis of Experimental Allergic Asthma. Journal of Immunology, 185, 6741-6752
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This work was supported by the National Institutes of Health grants HL-31963, GM-29507, GM-61656.
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Bosmann, M., Ward, P.A. (2012). Role of C3, C5 and Anaphylatoxin Receptors in Acute Lung Injury and in Sepsis. In: Lambris, J., Hajishengallis, G. (eds) Current Topics in Innate Immunity II. Advances in Experimental Medicine and Biology, vol 946. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0106-3_9
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