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  • Review Article
  • Published:

The dark side of C5a in sepsis

Nature Reviews Immunology volume 4, pages 133–142 (2004)Cite this article

Key Points

  • Complement activation can occur through three established pathways: classical, alternative and lectin, resulting in the cleavage of C3 and C5 to generate anaphylatoxin peptides (C3a and C5a) and C3b and C5b. C3b is a major phagocytosis-promoting product, whereas C5b interacts with C6–C9 to form the membrane-attack complex on cell membranes.

  • There is clear evidence of complement activation in sepsis, including increased serum levels of C3a, C5a and the soluble C5b–C9 complex. In addition, blood neutrophils show loss of C5a receptor (C5aR), reduced in vitro binding of C5a and loss of chemotactic responsiveness to C5a.

  • C5a, under normal circumstances and under conditions of regulated production, provides defensive functions by enhancing chemotactic responses of neutrophils, phagocytosis and the respiratory burst (production of H2O2) that is involved in killing bacteria.

  • During experimental sepsis, excessive production of C5a results in a series of harmful consequences: defective mitogen-activated protein kinase (MAPK) signalling in neutrophils and loss of chemotactic and phagocytic function, loss of the ability to contain bacteria in the tissues and the blood, and death.

  • In rodents with sepsis, blocking strategies directed against complement include blockade of C5a, blockade of C5aR or blockade of interleukin-6 (which upregulates C5aR). However, these strategies have not yet been successfully translated in human trials, possibly owing to the inability of rodent models to adequately recreate the events that occur in human sepsis.

Abstract

Sepsis is a major clinical problem for which therapeutic interventions have been largely unsuccessful, in spite of promising strategies that were successful in animals, especially rodents. There is new evidence that sepsis causes excessive activation of the complement system and that this induces paralysis of innate immune functions in phagocytic cells due to effects of the powerful complement-activation product, C5a. This review describes our present understanding of how and why sepsis is a life-threatening condition and how it might be more effectively treated.

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Figure 1: Schematic structures of human C5a and C5a receptor (C5aR).
Figure 2: Signalling pathways for C5a interaction with C5a receptor (C5aR) on neutrophils.
Figure 3: Under physiological conditions, low and locally contained levels of C5a have positive host defensive effects by 'priming' neutrophils and macrophages.
Figure 4: Outcomes of excessive generation of C5a, as occurs in sepsis, when relatively high levels (10–100 nM) of C5a are present in the plasma.

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Acknowledgements

Special thanks to R.-F. Guo for his assistance in preparation of the manuscript. Research was supported by grants from the National Institutes of Health, USA.

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Authors and Affiliations

  1. Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, 48109, Michigan, USA

    Peter A. Ward

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DATABASES

LocusLink

C3

C5

C5aR

CCL2

cPLA2

CRP

G-CSF

HMGB1

IL-1α

IL-1β

IL-6

IL-8

MBL

MIF

PAI1

PSGL1

TNF

Glossary

SEPSIS

The most recent definition of sepsis involves a body temperature >38.3°C or <36°C, heart rate >90 beats/minute, blood leukocyte count >12 × 109/litre, and evidence of bacterial infection but not necessarily bacteraemia. The range of classifications of sepsis include: systemic inflammatory response syndrome (SIRS), severe sepsis, septic shock and multi-organ failure.

BROAD-SPECTRUM ANTIBIOTICS

Drugs that kill a wide variety of bacteria or cause cessation of bacterial growth.

ANAPHYLATOXINS

Glycosylated peptides, C3a and C5a, generated during activation of the complement system, with molecular weights of ∼8,000 kDa. These peptides interact with rhodopsin-type receptors (C3a receptor and C5a receptor) on various cell types and induce features of acute inflammation, such as increased blood flow, oedema and smooth-muscle contraction.

CAECAL LIGATION AND PUNCTURE

(CLP). CLP involves ligation of the caecum in rats or mice followed by needle-induced perforation. This induces a state of sepsis with peritonitis and growth of intestine-derived bacteria in the peritoneal cavity, followed by presence of bacteria in the blood and various organs (for example, the liver, lungs and kidneys). The presence of mixed bacteria species (aerobic and anaerobic) is referred to as polymicrobial sepsis.

ISCHAEMIA-REPERFUSION INJURY

Partial or complete cessation of blood flow to an organ or tissue (ischaemia), followed by re-establishment of blood flow (reperfusion). The result is injury, which might be reversible or irreversible, depending on duration of ischaemia and the organ involved.

RHODOPSIN-TYPE RECEPTOR

A seven transmembrane-spanning structure in the cell membrane of a receptor with a cytoplasmic peptide linkage to G-proteins. When a ligand (agonist) interacts with the outer regions of the receptor, intracellular signalling occurs.

WEIBLE-PALADE GRANULES

Cytoplasmic granules in endothelial cells that contain the adhesion molecule, P-selectin, and the clotting factor, von-Willebrand factor (vWF). When endothelial cells are exposed to C5a or stimuli such as histamine, these granules fuse with the cell membrane, causing cell-surface expression of P-selectin and secretion of vWF.

MULTI-ORGAN FAILURE

Evidence of functional failure of numerous organs (for example, the liver, lungs and kidneys) during sepsis or shock, or both.

CYTOKINE/CHEMOKINE STORM

The presence of numerous cytokines (such as tumour-necrosis factor and interleukin-1, IL-1) and chemokines (such as IL-8 and CC-chemokine ligand 2) in the serum during sepsis. This has also been referred to as the systemic inflammatory response syndrome (SIRS).

CONSUMPTIVE COAGULOPATHY

A reduction in the levels of clotting factors in the plasma as a result of the depletion of these proteins through excessive activation of the clotting system. Under such conditions, the plasma often contains activated clotting factors and complexes (such as thrombin–anti-thrombin), indicating marked activation of the clotting system.

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Ward, P. The dark side of C5a in sepsis. Nat Rev Immunol 4, 133–142 (2004). https://doi.org/10.1038/nri1269

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