Abstract
Complement 5a (C5a) has been implicated in the pathogenesis of sepsis by inducing the functional impairment of neutrophils; however, the utility of C5a receptors (C5aRs; C5aR and C5L2) as biomarkers for the management of sepsis is uncertain. This study investigated the dynamic expression of C5aR and C5L2 on neutrophils and their effects on neutrophil function. We found that sepsis patients displayed low expression levels of C5aR and C5L2 on neutrophils compared to healthy and systemic inflammatory response syndrome (SIRS) subjects, and this expression pattern was correlated with disease severity. Additionally, the expression levels of C5aR and C5L2 were associated with the survival of sepsis patients. In vitro, the addition of C5a significantly reduced C5aR and C5L2 expression levels and IL-8 production in neutrophils from sepsis patients. Those findings suggest that the reduced expression of C5aRs was associated with the functional impairment of neutrophils and a poor prognosis for sepsis patients. Overall, these findings may help establish C5aRs expression levels as early markers to predict the severity of sepsis.
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References
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D et al. SCCM/ESICM/ACCP/ATS/SI:2001SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31: 1250–1256.
Balk RA . Severe sepsis and septic shock. Crit Care Clin 2000; 16: 179–192.
Angus DC, Wax RS . Epidemiology of sepsis: an update. Crit Care Med 2001; 29: S109–S116.
Andonegui G, Zhou H, Bullard D, Kelly MM, Mullaly SC, McDonald B et al. Mice that exclusively express TLR4 on endothelial cells can efficiently clear a lethal systemic Gram-negative bacterial infection. J Clin Invest 2009; 119: 1921–1930.
Brown KA, Treacher DF . Neutrophils as potential therapeutic targets in sepsis. Discov Med 2006; 6: 118–122.
Okinaga S, Slattery D, Humbles A, Zsengeller Z, Morteau O, Kinrade MB et al. C5L2, a nonsignaling C5A binding protein. Biochemistry 2003; 42: 9406–9415.
Li R, Coulthard LG, Wu MC, Taylor SM, Woodruff TM . C5L2: a controversial receptor of complement anaphylatoxin, C5a. FASEB J 2013; 27: 855–864.
Huber-Lang M, Sarma JV, Rittirsch D, Schreiber H, Weiss M, Flierl M et al. Changes in the novel orphan, C5a receptor (C5L2), during experimental sepsis and sepsis in humans. J Immunol 2005; 1174: 1104–1110.
Gressner OA, Koch A, Sanson E, Trautwein C, Tacke F . High C5a levels are associated with increased mortality in sepsis patients—no enhancing effect by actin-free Gc-globulin. Clin Biochem 2008; 41: 974–980.
Guo RF, Huber-Lang M, Wang X, Sarma V, Padgaonkar VA, Craig RA et al. Protective effects of anti-C5a in sepsis-induced thymocyte apoptosis. J Clin Invest 2000; 106: 1271–1280.
Bone RC, Balk RA, Cerra FB . Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis: the ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992; 101: 1644–1655.
Poehlmann H, Schefold JC, Zuckermann-Becker H, Volk HD, Meisel C . Phenotype changes and impaired function of dendritic cell subsets in patients with sepsis: a prospective observational analysis. Crit Care 2009; 13: R119.
Solomkin JS, Jenkins MK, Nelson RD, Chenoweth D, Simmons RL . Neutrophil dysfunction in sepsis. II. Evidence for the role of complement activation products in cellular deactivation. Surgery 1981; 90: 319–327.
Guo RF, Riedemann NC, Bernacki KD, Sarma VJ, Laudes IJ, Reuben JS et al. Neutrophil C5a receptor and the outcome in a rat model of sepsis. FASEB J 2003; 17: 1889–1891.
Unnewehr H, Rittirsch D, Sarma JV, Zetoune F, Flierl MA, Perl M et al. Changes and regulation of the C5a receptor on neutrophils during septic shock in humans. J Immunol 2013; 1908: 4215–4225.
Huber-Lang MS, Younkin EM, Sarma JV, McGuire SR, Lu KT, Guo RF et al. Complement-induced impairment of innate immunity during sepsis. J Immunol 2002; 169: 3223–3231.
Kim H, Erdman LK, Lu Z, Serghides L, Zhong K, Dhabangi A et al. Functional roles for C5a and C5aR, but not C5L2, in the pathogenesis of human and experimental cerebral malaria. Infect Immun 2014; 82: 371–379.
Wang R, Lu B, Gerard C, Gerard NP . Disruption of the complement anaphylatoxin receptor C5L2 exacerbates inflammation in allergic contact dermatitis. J Immunol 2013; 191: 4001–4009.
Guo RF, Riedemann NC, Laudes IJ, Ward PA . Altered neutrophil trafficking during sepsis. J Immunol 2002; 169: 307–314.
Riedemann NC, Guo RF, Ward PA . A key role of C5a/C5aR activation for the development of sepsis. J Leukoc Biol 2003; 74: 966–970.
Conway MA, Kefala K, Wilkinson TS, Dhaliwal K, Farreii L, Walsh T et al. C5a mediates peripheral blood neutrophil dysfunction in critically ill patients. Am J Respir Crit Care Med 2009; 180: 19–28.
Wasmuth HE, Kunz D, Yagmur E, Timmer-Stranghöner A, Vidacek D, Siewert E et al. Patients with acute on chronic liver failure display “sepsis-like” immune paralysis. J Hepatol 2005; 42: 195–201.
Döcke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 1997; 3: 678–681.
Conway MA, Anderson N, Brittan M, Wilkinson TS, McAuley DF, Antonelli J et al. Combined dysfunctions of immune cells predict nosocomial infection in critically ill patients. Br J Anaesth 2013; 111: 778–787.
Acknowledgements
We appreciate all septic individuals, SIRS individuals and healthy participants in this study. The study was approved and has been reviewed by the ethics committee of our 302 Hospital. This work was supported by grants from the National Science Fund for Outstanding Young Scholars (No. 81222024), the National Science Fund for Distinguished Young Scholars (No. 81400626) and the Beijing Natural Science Foundation (No. 714428).
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Xu, R., Lin, F., Bao, C. et al. Complement 5a receptor-mediated neutrophil dysfunction is associated with a poor outcome in sepsis. Cell Mol Immunol 13, 103–109 (2016). https://doi.org/10.1038/cmi.2014.136
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DOI: https://doi.org/10.1038/cmi.2014.136
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