Regulatory role of C5a in LPS‐induced IL‐6 production by neutrophils during sepsis

Abstract

Experimental sepsis in rodents occurring after cecal ligation/puncture (CLP) is associated with excessive complement activation and a systemic inflammatory response. The proinflammatory mediator IL-6 has recently been shown to be an important inducer of the C5a receptor (C5aR) during sepsis. We now provide evidence that serum IL-6 production during sepsis in rats was reduced in neutrophil-depleted animals and that absence of C5aR in mice as well as antibody-blockade of C5a in rats significantly reduced serum levels of IL-6 during sepsis. Lipopolysaccharide (LPS)-induced production in vitro of IL-6 by neutrophils was significantly enhanced in the co-presence of C5a, likely due to transcriptional up-regulation of IL-6. Production of IL-6 in neutrophils by LPS was NF-kappaB dependent (but not on the presence of p50) and dependent on phosphorylation of p38-mitogen activated protein kinase (MAPK) as well as p44/p42 MAPK (ERK1/2) but not on phosphorylation of c-Jun N-terminal kinases (JNK1/2). C5a stimulation of neutrophils elicited a rapid phosphorylation of ERK1/2 and p38 MAPK. Accordingly, we suggest that induction of IL-6 after CLP is neutrophil and C5a/C5aR dependent, likely due to the ability of C5a to cause activation of ERK1/2 and p38 MAPK signaling pathways.

C5a-Blockade Improves Burn-Induced Cardiac Dysfunction

“…However, excessive and unregulated generation of C5a, which impairs contractility as seen in sepsis, results in defective cardiac function (18). Analogous to this would be our studies in sepsis in which low levels of C5a prime neutrophils for enhanced innate immune functions while high levels of C5a cause a loss of MAPK signaling pathways and greatly impaired innate immune function (26).…”

“…We have previously reported that C5a plays an important role in enhancing MIF release from neutrophils, which may explain the restored cardiac performance by a blockade of C5a after burn injury (44). Also, we and others have reported that C5a induces the phosphorylation of p38 and other MAPKs as well as the up-regulation of NF-B (17,26). Therefore, the cardioprotective effects seen after a blockade of C5a may be partially due to inhibition of these intracellular signaling pathways.…”

“…There are no published data that definitively support a direct linkage or intersection between the C5aR and TLR4 pathways (16,42,43). However, there are several reports that indicate the ability of C5a to alter the outcomes of LPS-induced activation of phagocytic cells (16,26,44,45). Recently, it has been reported that the induction of the IL-12 family of cytokines in activated macrophages was suppressed in the copresence of C5a, potentially setting the stage for the immunosuppressive effects seen in sepsis (18).…”

Candidate inhibitors of porcine complement

“…The effects of binding of C5a or C5a desArg to their receptors depend on the cell type expressing them. C5a is known to have a range of effects on the innate immune cells in particular neutrophils and macrophages: it is a chemoattractant and enhance expression of adhesion molecules on the cells both of which are important to direct the phagocytes from the blood to the site of infection/injury (80,81); the molecule induce phagocytosis and the consecutive oxidative burst to kill the phagocytized microorganisms (64), and it releases enzymes from intracellular granules as well as induces production and release of cytokines (82)(83)(84). The effect of C5aR binding of C5a is most extensively studied while the role of C5L2 is less well understood, although recent studies have indicated both important pro-and anti-inflammatory effects of the C5L2 receptor (85,86).…”

Increased concentration of the complement split product C5a in acute pyelonephritis during pregnancy

“…Anaphylatoxins C3a, C4a and C5a are proinflammatory peptides released from the cleavage of their native components following activation of the complement cascade. These molecules induce vascular permeability [2][3][4], smooth muscle contraction [3][4][5], the release of pro-inflammatory cytokines [6][7][8] and white blood cell chemotaxis [9][10][11]. Among anaphylatoxins, C5a is the most potent [4].…”