Regulation of IL-8 production by complement-activated product, C5a, in vitro and in vivo during sepsis

Wang, Liyan; Han, Gencheng; Wang, Renxi; Chen, Guojiang; Xu, Ruonan; Xiao, He; Li, Xia; Geng, Shaoxia; Li, Yurong; Li, Xinying; Wang, Jianan; Feng, Jiannan; Riedemann, Niels C.; Guo, Renfeng; Shen, Beifen; Li, Yan

doi:10.1016/j.clim.2010.05.012

Cited by 28 publications

(24 citation statements)

References 29 publications

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“…In contrast, when kidneys from wild-type mice were transplanted into C3 -/-mice, renal allograft rejection could not be prevented (44). Also, absence of local C3 synthesis by the donor kidney, instead of circulating C3 by the recipient, was found to prevent complement-mediated reperfusion damage (45). These results indicate that not circulating C3 in the recipient but locally produced C3 by the donor kidney is an important mediator of early post-reperfusion and late rejection associated allograft injury.…”

Section: Complement Activation By the Donormentioning

confidence: 96%

Crosstalk between Complement and Toll-like Receptor Activation in Relation to Donor Brain Death and Renal Ischemia-Reperfusion Injury

Damman¹,

Daha

Son

et al. 2011

American Journal of Transplantation

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Section: Complement Activation By the Donormentioning

confidence: 96%

Crosstalk between Complement and Toll-like Receptor Activation in Relation to Donor Brain Death and Renal Ischemia-Reperfusion Injury

Damman¹,

Daha

Son

et al. 2011

American Journal of Transplantation

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“…These effects were primarily mediated by the C5aR and involved necrosis factor κB activation and the mitogen-activated protein kinases (MAPK) extracellular regulated kinase 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK). 20 In models of whole human blood and a mouse model of encephalitis, Wang et al 19 suggest a regulator role for complement in TLR4-induced cytokine responses. They describe C5a as an amplifier of IL-8–dependent responses in humans and of IL-6 and KC in mice and implicate the MAPKs p38 and ERK1/2 as mediators.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, C5a enhancement of TLR-dependent responses is not restricted to TLR4 but has been described with TLR2- and TLR9-mediated responses. 19,20 …”

Section: Discussionmentioning

confidence: 99%

Complement mediates a primed inflammatory response after traumatic lung injury

Hoth¹,

Wells²,

Jones³

et al. 2014

Journal of Trauma and Acute Care Surgery

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BACKGROUND Pulmonary contusion (PC) is a common, potentially lethal injury that results in the priming for exaggerated responses to subsequent immune challenge such as an infection (second hit). We hypothesize a PC-induced complement (C) activation participates in the priming effect for a second hit. METHODS Male, 8 weeks to 9 weeks, C57BL/6 mice (wild-type, C5−/−) underwent blunt chest trauma resulting in PC. At 3 hours/24 hours after injury, the inflammatory response was measured in tissue, serum, and bronchoalveolar lavage (BAL). The thrombin inhibitor, hirudin, was used to determine if injury-induced thrombin participated in the activation of C. Injury-primed responses were tested by challenging injured mice with bacterial endotoxin (lipopolysaccharide, LPS) as a second hit. Inflammatory responses were assessed at 4 hours after LPS challenge. Data were analyzed using one-way analysis of variance with Bonferroni multiple comparison posttest (significance, p ≤ 0.05). Protocols were approved by the Institutional Animal Care and Use Committee. RESULTS We found significantly increased levels of C5a in the BAL of injured animals as early as 24 hours, persisting for up to 72 hours after injury. Hirudin-treated injured mice had significantly decreased levels of thrombin in the BAL that correlated with reduced C5a levels. Injured mice challenged with intratracheal (IT) LPS had increased C5a and inflammatory response. Conversely, inhibition of C5a or its receptor, C5aR, before LPS challenge correlated with decreased inflammatory responses; C5a-deficient mice showed a similar loss of primed response to LPS challenge. CONCLUSION Complement C5a levels in the BAL are increased over several days after PC. Premorbid inhibition of thrombin markedly decreases C5a levels after PC, suggesting that thrombin-induced C activation is the major pathway of activation after PC. Similarly, inhibition of C5a after PC will decrease injury-primed responses to LPS stimulation. Our findings suggest cross-talk between the coagulation and complement systems that induce immune priming after PC.

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“…Furthermore, secretion of IL-8, a strong chemoattractant for PMN that is able to activate and degranulate PMN, was completely regulated by C5a following one hour and at least partially following longer incubation. Similarly, C5a has been shown to strongly increase IL-8 release from human whole-blood cells induced by LPS and other types of TLR agonists and to be involved in E. coli-induced IL-8 release during whole-blood infection (34), indicating the effects of C5a on IL-8 to be broad. In addition, recent data by Cheng et al demonstrated a role for C5a in C. albicans-induced proinflammatory cytokine production by human PBMCs (22), which further supports the theory of the contribution of C5a in a broad spectrum of inflammatory responses caused by various types of pathogens.…”

Section: Discussionmentioning

confidence: 99%

A Second Stimulus Required for Enhanced Antifungal Activity of Human Neutrophils in Blood Is Provided by Anaphylatoxin C5a

Hünniger

Bieber

Martin

et al. 2015

The Journal of Immunology

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Polymorphonuclear neutrophilic granulocytes (PMN) as cellular components of innate immunity play a crucial role in the defense against systemic Candida albicans infection. To analyze stimuli that are required for PMN activity during C. albicans infection in a situation similar to in vivo, we used a human whole-blood infection model. In this model, PMN activation 10 min after C. albicans infection was largely dependent on the anaphylatoxin C5a. Most importantly, C5a enabled blood PMN to overcome filament-restricted recognition of C. albicans and allowed efficient elimination of nonfilamentous C. albicans cph1Δ/efg1Δ from blood. Major PMN effector mechanisms, including oxidative burst, release of secondary granule contents and initial fungal phagocytosis could be prevented by blocking C5a receptor signaling. Identical effects were achieved using a humanized Ab specifically targeting human C5a. Phagocytosis of C. albicans 10 min postinfection was mediated by C5a-dependent enhancement of CD11b surface expression on PMN, thus establishing the C5a-C5aR-CD11b axis as a major modulator of early anti-Candida immune responses in human blood. In contrast, phagocytosis of C. albicans by PMN 60 min postinfection occurred almost independently of C5a and mainly contributed to activation of phagocytically active PMN at later time points. Our results show that C5a is a critical mediator in human blood during C. albicans infection.

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Regulation of IL-8 production by complement-activated product, C5a, in vitro and in vivo during sepsis

Cited by 28 publications

References 29 publications

Crosstalk between Complement and Toll-like Receptor Activation in Relation to Donor Brain Death and Renal Ischemia-Reperfusion Injury

Crosstalk between Complement and Toll-like Receptor Activation in Relation to Donor Brain Death and Renal Ischemia-Reperfusion Injury

Complement mediates a primed inflammatory response after traumatic lung injury

A Second Stimulus Required for Enhanced Antifungal Activity of Human Neutrophils in Blood Is Provided by Anaphylatoxin C5a

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