Skip to main content
SpringerLink
Log in
Book cover

Current Topics in Innate Immunity II pp 147–159Cite as

Role of C3, C5 and Anaphylatoxin Receptors in Acute Lung Injury and in Sepsis

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 946))

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.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Gerard, N.P., and Gerard, C. (1991). The chemotactic receptor for human C5a anaphylatoxin. Nature, 349, 614-617

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Ravetch, J.V., and Clynes, R.A. (1998). Divergent roles for Fc receptors and complement in vivo. Annual Review of Immunology, 16, 421-432

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Seekamp, A., and Ward, P.A. (1993). Ischemia-reperfusion injury. Agents & Actions - Supplements, 41, 137-152

    CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Ward, P.A. (1996). Rous-Whipple Award Lecture. Role of complement in lung inflammatory injury. American Journal of Pathology, 149, 1081-1086

    PubMed  CAS  Google Scholar 

  • Ward, P.A. (2010). The Harmful Role of C5a on Innate Immunity in Sepsis. Journal of Innate Immunity, 2, 439-445

    Article  PubMed  CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Institutes of Health grants HL-31963, GM-29507, GM-61656.

Author information

Authors and Affiliations

  1. Department of Pathology, University of Michigan Medical School, 1301 Catherine Rd., Box 5602, 48109-5602, Ann Arbor, MI, USA

    Markus Bosmann & Peter A. Ward

Authors
  1. Markus Bosmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter A. Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter A. Ward .

Editor information

Editors and Affiliations

  1. Department Of Pathology Laboratory Of, Medicine, University Of Pennsylvania, Johnson Pavilion 410, Philadelphia, 19104, Pennsylvania, USA

    John D. Lambris

  2. Health Sciences Center, University of Louisville, Louisville, 40292, Kentucky, USA

    George Hajishengallis

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

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

Download citation

Publish with us

Policies and ethics

Search

Navigation