A narrative review of the role of the complement system in sepsis

Abstract

Sepsis is a common syndrome with a high mortality rate worldwide, characterized by complex physiological, pathological, and biochemical abnormalities. The complement system, an essential component of innate immunity, consists of approximately 30 proteins that undergo a series of cascading enzymatic reactions to form a membrane attack complex, leading to cell lysis. Sepsis-induced complement activation drives endothelial cells toward a proinflammatory and prothrombotic phenotype. This review highlights the complex interactions among the complement, coagulation, and inflammatory systems, examines the prognostic significance of complement activation in patients with sepsis, and discusses the potential clinical applications of complement inhibitors.

Keywords

Coagulation / Complement system / Endothelial cells / Sepsis

Conflict of interest statement

The authors declare no conflict of interest.

Author contributions

Zhu L wrote the original draft. Both authors contributed to writing, reviewing, and editing.

Funding

None.

Ethical approval of studies and informed consent

Not applicable.

Acknowledgements

None.

References

[1] Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016; 315(8):801-810. doi:10.1001/jama.2016.0287.

[2] Ward PA, Guo RF, Riedemann NC. Manipulation of the complement system for benefit in sepsis. Crit Care Res Pract. 2012; 2012:427607. doi:10.1155/2012/427607.

[3] Song WC. Crosstalk between complement and toll-like receptors. Toxicol Pathol. 2012; 40(2):174-182. doi:10.1177/0192623311428478.

[4] Rittirsch D, Redl H, Huber-Lang M. Role of complement in multiorgan failure. Clin Dev Immunol. 2012; 2012:962927. doi:10.1155/2012/962927.

[5] Krem MM, Di Cera E. Evolution of enzyme cascades from embryonic development to blood coagulation. Trends Biochem Sci. 2002; 27(2):67-74. doi:10.1016/s0968-0004(01)02007-2.

[6] Lendak D, Mihajlovic D, Mitic G, et al. Complement component consumption in sepsis correlates better with hemostatic system parameters than with inflammatory biomarkers. Thromb Res. 2018; 170:126-132. doi:10.1016/j.thromres.2018.08.013.

[7] Bosmann M, Ward PA. Role of C3, C5 and anaphylatoxin receptors in acute lung injury and in sepsis. Adv Exp Med Biol. 2012; 946:147-159. doi:10.1007/978-1-4614-0106-3_9.

[8] Markiewski MM, DeAngelis RA, Lambris JD. Complexity of complement activation in sepsis. J Cell Mol Med. 2008; 12(6A):2245-2254. doi:10.1111/j.1582-4934.2008.00504.x.

[9] Denk S, Neher MD, Messerer DAC, et al. Complement C5a functions as a master switch for the pH balance in neutrophils exerting fundamental immunometabolic effects. J Immunol. 2017; 198(12):4846-4854. doi:10.4049/jimmunol.1700393.

[10] Hansen MB, Rasmussen LS, Pilely K, et al. The lectin complement pathway in patients with necrotizing soft tissue infection. J Innate Immun. 2016; 8(5):507-516. doi:10.1159/000447327.

[11] Zhao X, Chen YX, Li CS. The prognostic performance of the complement system in septic patients in emergency department: a cohort study. Biomark Med. 2015; 9(7):661-668. doi:10.2217/bmm.15.32.

[12] Zhao X, Chen YX, Li CS. Predictive value of the complement system for sepsis-induced disseminated intravascular coagulation in septic patients in emergency department. J Crit Care. 2015; 30(2):290-295. doi:10.1016/j.jcrc.2014.11.007.

[13] Garred P, Genster N, Pilely K, et al. A journey through the lectin pathway of complement-MBL and beyond. Immunol Rev. 2016; 274(1):74-97. doi:10.1111/imr.12468.

[14] Gavriilaki E, Ho VT, Schwaeble W, et al. Role of the lectin pathway of complement in hematopoietic stem cell transplantation-associated endothelial injury and thrombotic microangiopathy. Exp Hematol Oncol. 2021; 10(1):57. doi:10.1186/s40164-021-00249-8.

[15] Amara U, Rittirsch D, Flierl M, et al. Interaction between the coagulation and complement system. Adv Exp Med Biol. 2008; 632:71-79. doi:10.1007/978-0-387-78952-1_6.

[16] Liszewski MK, Atkinson JP. Too much of a good thing at the site of tissue injury: the instructive example of the complement system predisposing to thrombotic microangiopathy. Hematology Am Soc Hematol Educ Program. 2011; 2011:9-14. doi:10.1182/asheducation-2011.1.9.

[17] Halbgebauer R, Schmidt CQ, Karsten CM, Ignatius A, Huber-Lang M. Janus face of complement-driven neutrophil activation during sepsis. Semin Immunol. 2018; 37:12-20. doi:10.1016/j.smim.2018.02.004.

[18] West EE, Kunz N, Kemper C. Complement and human T cell metabolism: location, location, location. Immunol Rev. 2020; 295(1):68-81. doi:10.1111/imr.12852.

[19] Thorgersen EB, Barratt-Due A, Haugaa H, et al. The role of complement in liver injury, regeneration, and transplantation. Hepatology. 2019; 70(2):725-736. doi:10.1002/hep.30508.

[20] Kruger-Genge A, Blocki A, Franke RP, Jung F. Vascular endothelial cell biology: an update. Int J Mol Sci. 2019; 20(18):4411. doi:10.3390/ijms20184411.

[21] Chang JC. Molecular pathogenesis of endotheliopathy and endotheliopathic syndromes, leading to inflammation and microthrombosis, and various hemostatic clinical phenotypes based on “two-activation theory of the endothelium” and “two-path unifying theory” of hemostasis. Medicina (Kaunas). 2022; 58(9):1311. doi:10.3390/medicina58091311.

[22] Brunn GJ, Saadi S, Platt JL. Differential regulation of endothelial cell activation by complement and interleukin 1alpha. Circ Res. 2006; 98(6):793-800. doi:10.1161/01.RES.0000216071.87981.16.

[23] Joffre J, Hellman J, Ince C, Ait-Oufella H. Endothelial responses in sepsis. Am J Respir Crit Care Med. 2020; 202(3):361-370. doi:10.1164/rccm.201910-1911TR.

[24] Laboux T, Maanaoui M, Allain F, et al. Hemolysis is associated with altered heparan sulfate of the endothelial glycocalyx and with local complement activation in thrombotic microangiopathies. Kidney Int. 2023; 104(2):353-366. doi:10.1016/j.kint.2023.03.039.

[25] Zeller J, Bogner B, Kiefer J, et al. CRP enhances the innate killing mechanisms phagocytosis and ROS formation in a conformation and complement-dependent manner. Front Immunol. 2021; 12:721887. doi:10.3389/fimmu.2021.721887.

[26] Zhang H, Wang Y, Qu M, et al. Neutrophil, neutrophil extracellular traps and endothelial cell dysfunction in sepsis. Clin Transl Med. 2023; 13(1):e1170. doi:10.1002/ctm2.1170.

[27] Joffre J, Hellman J. Oxidative stress and endothelial dysfunction in sepsis and acute inflammation. Antioxid Redox Signal. 2021; 35(15):1291-1307. doi:10.1089/ars.2021.0027.

[28] Larsen SB, Cowley CJ, Fuchs E. Epithelial cells: liaisons of immunity. Curr Opin Immunol. 2020; 62:45-53. doi:10.1016/j.coi.2019.11.004.

[29] Sorbara MT, Foerster EG, Tsalikis J, et al. Complement C3 drives autophagy-dependent restriction of cyto-invasive bacteria. Cell Host Microbe. 2018; 23(5):644-652.e5. doi:10.1016/j.chom.2018.04.008.

[30] Tam JC, Bidgood SR, McEwan WA, James LC. Intracellular sensing of complement C3 activates cell autonomous immunity. Science. 2014; 345(6201):1256070. doi:10.1126/science.1256070.

[31] Liszewski MK, Atkinson JP. Membrane cofactor protein (MCP; CD46): deficiency states and pathogen connections. Curr Opin Immunol. 2021; 72:126-134. doi:10.1016/j.coi.2021.04.005.

[32] Fattahi F, Zetoune FS, Ward PA. Complement as a major inducer of harmful events in infectious sepsis. Shock. 2020; 54(5):595-605. doi:10.1097/SHK.0000000000001531.

[33] Keshari RS, Silasi R, Lupu C, Taylor FB Jr, Lupu F. In vivo-generated thrombin and plasmin do not activate the complement system in baboons. Blood. 2017; 130(24):2678-2681. doi:10.1182/blood-2017-06-788216.

[34] Subramaniam S, Jurk K, Hobohm L, et al. Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development. Blood. 2017; 129(16):2291-2302. doi:10.1182/blood-2016-11-749879.

[35] Davis AE 3rd, Mejia P, Lu F. Biological activities of C1 inhibitor. Mol Immunol. 2008; 45(16):4057-4063. doi:10.1016/j.molimm.2008.06.028.

[36] Amara U, Flierl MA, Rittirsch D, et al. Molecular intercommunication between the complement and coagulation systems. J Immunol. 2010; 185(9):5628-5636. doi:10.4049/jimmunol.0903678.

[37] Ehrnthaller C, Ignatius A, Gebhard F, Huber-Lang M. New insights of an old defense system: structure, function, and clinical relevance of the complement system. Mol Med. 2011; 17(3-4):317-329. doi:10.2119/molmed.2010.00149.

[38] Ikeda K, Nagasawa K, Horiuchi T, Tsuru T, Nishizaka H, Niho Y. C5a induces tissue factor activity on endothelial cells. Thromb Haemost. 1997; 77(2):394-398.

[39] Dobo J, Harmat V, Beinrohr L, Sebestyen E, Zavodszky P, Gal P. MASP-1, a promiscuous complement protease: structure of its catalytic region reveals the basis of its broad specificity. J Immunol. 2009; 183(2):1207-1214. doi:10.4049/jimmunol.0901141.

[40] Jenny L, Noser D, Larsen JB, et al. MASP-1 of the complement system alters fibrinolytic behaviour of blood clots. Mol Immunol. 2019; 114:1-9. doi:10.1016/j.molimm.2019.07.005.

[41] Krarup A, Wallis R, Presanis JS, Gal P, Sim RB. Simultaneous activation of complement and coagulation by MBL-associated serine protease 2. PLoS One. 2007; 2(7):e623. doi:10.1371/journal.pone.0000623.

[42] Hess K, Ajjan R, Phoenix F, Dobó J, Gál P, Schroeder V. Effects of MASP-1 of the complement system on activation of coagulation factors and plasma clot formation. PLoS One. 2012; 7(4):e35690. doi:10.1371/journal.pone.0035690.

[43] Oncul S, Afshar-Kharghan V. The interaction between the complement system and hemostatic factors. Curr Opin Hematol. 2020; 27(5):341-352. doi:10.1097/MOH.0000000000000605.

[44] Ritis K, Doumas M, Mastellos D, et al. A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol. 2006; 177(7):4794-4802. doi:10.4049/jimmunol.177.7.4794.

[45] Wojta J, Kaun C, Zorn G, et al. C5a stimulates production of plasminogen activator inhibitor-1 in human mast cells and basophils. Blood. 2002; 100(2):517-523. doi:10.1182/blood.v100.2.517.

[46] Naito M, Taguchi O, Kobayashi T, et al. Thrombin-activatable fibrinolysis inhibitor protects against acute lung injury by inhibiting the complement system. Am J Respir Cell Mol Biol. 2013; 49(4):646-653. doi:10.1165/rcmb.2012-0454OC.

[47] Peerschke EI, Reid KB, Ghebrehiwet B. Platelet activation by C1q results in the induction of alpha IIb/beta 3 integrins (GPIIb-IIIa) and the expression of P-selectin and procoagulant activity. J Exp Med. 1993; 178(2):579-587. doi:10.1084/jem.178.2.579.

[48] Abe T, Kubo K, Izumoto S, et al. Complement activation in human sepsis is related to sepsis-induced disseminated intravascular coagulation. Shock. 2020; 54(2):198-204. doi:10.1097/SHK.0000000000001504.

[49] Wiegner R, Chakraborty S, Huber-Lang M. Complement-coagulation crosstalk on cellular and artificial surfaces. Immunobiology. 2016; 221(10):1073-1079. doi:10.1016/j.imbio.2016.06.005.

[50] Kourtzelis I, Markiewski MM, Doumas M, et al. Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood. 2010; 116(4):631-639. doi:10.1182/blood-2010-01-264051.

[51] Storm BS, Christiansen D, Fure H, et al. Air bubbles activate complement and trigger hemostasis and C3-dependent cytokine release ex vivo in human whole blood. J Immunol. 2021; 207(11):2828-2840. doi:10.4049/jimmunol.2100308.

[52] Robertson N, Rappas M, Doré AS, et al. Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727. Nature. 2018; 553(7686):111-114. doi:10.1038/nature25025.

[53] Das A, Behera LM, Rana S. Interaction of human C5a with the major peptide fragments of C5aR1: direct evidence in support of “two-site” binding paradigm. ACS Omega. 2021; 6(35):22876-22887. doi:10.1021/acsomega.1c03400.

[54] Ward PA. The harmful role of c5a on innate immunity in sepsis. J Innate Immun. 2010; 2(5):439-445. doi:10.1159/000317194.

[55] van der Velden S, van Osch TLJ, Seghier A, et al. Complement activation drives antibody-mediated transfusion-related acute lung injury via macrophage trafficking and formation of NETs. Blood. 2024; 143(1):79-91. doi:10.1182/blood.2023020484.

[56] Karasu E, Demmelmaier J, Kellermann S, et al. Complement C5a induces pro-inflammatory microvesicle shedding in severely injured patients. Front Immunol. 2020; 11:1789. doi:10.3389/fimmu.2020.01789.

[57] Leffler J, Martin M, Gullstrand B, et al. Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J Immunol. 2012; 188(7):3522-3531. doi:10.4049/jimmunol.1102404.

[58] Hansen CB, Bayarri-Olmos R, Kristensen MK, Pilely K, Hellemann D, Garred P. Complement related pattern recognition molecules as markers of short-term mortality in intensive care patients. J Infect. 2020; 80(4):378-387. doi:10.1016/j.jinf.2020.01.010.

[59] Larsen JB, Laursen MA, Hvas CL, Larsen KM, Thiel S, Hvas AM. Reduced mannose-binding lectin-associated serine protease (MASP)-1 is associated with disturbed coagulation in septic shock. Thromb Haemost. 2019; 119(6):952-961. doi:10.1055/s-0039-1685140.

[60] Hedetoft M, Madsen MB, Hansen CB, Hyldegaard O, Garred P. Increase in the complement activation product C4d and the terminal complement complex sC5b-9 is associated with disease severity and a fatal outcome in necrotizing soft-tissue infection. J Innate Immun. 2022; 14(4):355-365. doi:10.1159/000520496.

[61] Flierl MA, Rittirsch D, Nadeau BA, et al. Functions of the complement components C3 and C5 during sepsis. FASEB J. 2008; 22(10):3483-3490. doi:10.1096/fj.08-110595.

[62] Eichenberger EM, Dagher M, Ruffin F, et al. Complement levels in patients with bloodstream infection due to Staphylococcus aureus or Gram-negative bacteria. Eur J Clin Microbiol Infect Dis. 2020; 39(11):2121-2131. doi:10.1007/s10096-020-03955-z.

[63] Hecke F, Schmidt U, Kola A, Bautsch W, Klos A, Kohl J. Circulating complement proteins in multiple trauma patients - correlation with injury severity, development of sepsis, and outcome. Crit Care Med. 1997; 25(12):2015-2024. doi:10.1097/00003246-199712000-00019.

[64] Xu RN, Lin F, Bao C, et al. Complement 5a receptor-mediated neutrophil dysfunction is associated with a poor outcome in sepsis. Cell Mol Immunol. 2016; 13(1):103-109. doi:10.1038/cmi.2014.136.

[65] de Nooijer AH, Kotsaki A, Kranidioti E, et al. Complement activation in severely ill patients with sepsis: no relationship with inflammation and disease severity. Crit Care. 2023; 27(1):63. doi:10.1186/s13054-023-04344-6.

[66] Bain W, Li HH, van der Geest R, et al. Increased alternative complement pathway function and improved survival during critical illness. Am J Respir Crit Care Med. 2020; 202(2):230-240. doi:10.1164/rccm.201910-2083OC.

[67] Garred P, Tenner AJ, Mollnes TE. Therapeutic targeting of the complement system: from rare diseases to pandemics. Pharmacol Rev. 2021; 73(2):792-827. doi:10.1124/pharmrev.120.000072.

[68] Diurno F, Numis FG, Porta G, et al. Eculizumab treatment in patients with COVID-19: preliminary results from real life ASL Napoli 2 Nord experience. Eur Rev Med Pharmacol Sci. 2020; 24(7):4040-4047. doi:10.26355/eurrev_202004_20875.

[69] Keshari RS, Silasi R, Popescu NI, et al. Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis. Proc Natl Acad Sci U S A. 2017; 114(31):E6390-E6399. doi:10.1073/pnas1706818114..

[70] McNamara LA, Topaz N, Wang X, Hariri S, Fox L, MacNeil JR. High risk for invasive meningococcal disease among patients receiving eculizumab (Soliris) despite receipt of meningococcal vaccine. Am J Transplant. 2017; 17(9):2481-2485. doi:10.1111/ajt.14426.

[71] Muenstermann M, Strobel L, Klos A, et al. Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections. Virulence. 2019; 10(1):677-694. doi:10.1080/21505594.2019.1640035.

[72] Sommerfeld O, Medyukhina A, Neugebauer S, et al. Targeting complement C5a receptor 1 for the treatment of immunosuppression in sepsis. Mol Ther. 2021; 29(1):338-346. doi:10.1016/j.ymthe.2020.09.008.

[73] Herrmann JB, Muenstermann M, Strobel L, et al. Complement C5a receptor 1 exacerbates the pathophysiology of sepsis and is a potential target for disease treatment. mBio. 2018; 9(1):e01755-e01717. doi:10.1128/mBio.01755-17.

[74] Hirose T, Ogura H, Takahashi H, et al. Serial change of C1 inhibitor in patients with sepsis: a prospective observational study. J Intensive Care. 2018; 6:37. doi:10.1186/s40560-018-0309-5.

[75] Landsem A, Nielsen EW, Fure H, et al. C1-inhibitor efficiently inhibits Escherichia coli-induced tissue factor mRNA up-regulation, monocyte tissue factor expression and coagulation activation in human whole blood. Clin Exp Immunol. 2013; 173(2):217-229. doi:10.1111/cei.12098.

[76] Davis AE 3rd, Cai S, Liu D. C 1 inhibitor: biologic activities that are independent of protease inhibition. Immunobiology. 2007; 212(4-5):313-323. doi:10.1016/j.imbio.2006.10.003.