INCREASED C5a RECEPTOR EXPRESSION IN SEPSIS.

Riedemann, Niels C.; Guo, Ruocheng; Neff, Thomas; Laudes, Ines J.; Keller, Kathy; Lambris, J. D.; Ward, Peter A.

doi:10.1097/00024382-200206001-00139

Cited by 22 publications

(43 citation statements)

References 13 publications

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“…Accumulating evidence suggests that excessive production of C5a in sepsis may contribute to the loss of C5a binding on neutrophils, decreased chemotactic responsiveness, defective oxidative burst, and impaired bacteriocidal activity (7,27,28,37). Blockade of C5a and its counter partner C5aR improves the outcome of septic animals, underscoring the importance of C5a-C5aR signaling in the innate immunity (7,22). The crucial role of C5aR signaling was directly revealed by using a whole blood model of inflammation (25).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, in a mouse model of CLP-induced sepsis C5aR expression is markedly increased in lung, liver, kidney, and heart, associated with up-regulation of C5aR mRNA. In this model, systemic blockade of C5aR with anti-C5aR antibody significantly improved survival rates (22). The pathophysiological importance of C5aR is reinforced by anti-inflammatory activities of a C5a receptor antagonist in reverse-passive Arthus reaction and endotoxic shock in rats (23,24).…”

mentioning

confidence: 83%

“…In CLP-induced sepsis, C5a expression is markedly enhanced in lung, liver, kidney, and heart in a transcription-dependent manner (22). To determine the mechanism by which C5aR content on neutrophils is regulated during sepsis, we evaluated C5aR protein and mRNA levels in purified neutrophils 0, 24, and 48 h after CLP.…”

Section: Internalization and Reconstitution Of C5ar On Neutrophils Dumentioning

confidence: 99%

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Neutrophil C5a receptor and the outcome in a rat model of sepsis

et al. 2003

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Complement fragment 5a (C5a)-C5a receptor (C5aR) signaling plays an essential role in neutrophil innate immunity. Blockade of either the ligand or the receptor improves survival rates in experimental sepsis. In the current study, sepsis was induced in rats by cecal ligation/puncture. Early in sepsis C5aR content on neutrophils significantly dropped, reached the nadir at 24 h after onset of sepsis, and progressively elevated thereafter. Western-blot, RT-PCR, and confocal microscopy analyses revealed that the loss and re-expression of C5aR during sepsis might be due, at least in part, to the receptor internalization and reconstitution. The reduction and reconstitution of C5aR correlate with the loss and restoration of innate immune functions of blood neutrophils (chemotaxis and reactive oxygen species production), respectively. Quantitative measurements of C5aR on blood neutrophils are highly predictive of survival or death during sepsis. These data suggest that neutrophil C5aR content represents an essential component of an efficient defense system in sepsis and may serve as a prognostic marker for the outcome.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 83%

Section: Internalization and Reconstitution Of C5ar On Neutrophils Dumentioning

confidence: 99%

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Neutrophil C5a receptor and the outcome in a rat model of sepsis

et al. 2003

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“…The C5aR has also been found in glial cells [81,82], cerebellar granule cells [83], vascular endothelial cells [84e86] and in cells of liver and lung [87,88]. Its expression is up-regulated in regenerating hepatocytes [89] and, during the early phase of sepsis, in heart tissue [90]. C5L2 transcripts were observed in many organs and tissues including heart, lung, spleen, liver, placenta, skeletal muscle, bone marrow [73], and several regions of the brain [91].…”

Section: Cell Type Distribution Of the Members Of Fpr And C5ar Familiesmentioning

confidence: 99%

The N-formyl peptide receptors and the anaphylatoxin C5a receptors: An overview

2007

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Leukocyte recruitment to sites of inflammation and infection is dependent on the presence of a gradient of locally produced chemotactic factors. This review is focused on current knowledge about the activation and regulation of chemoattractant receptors. Emphasis is placed on the members of the N-formyl peptide receptor family, namely FPR (N-formyl peptide receptor), FPRL1 (FPR like-1) and FPRL2 (FPR like-2), and the complement fragment C5a receptors (C5aR and C5L2). Upon chemoattractant binding, the receptors transduce an activation signal through a G protein-dependent pathway, leading to biochemical responses that contribute to physiological defense against bacterial infection and tissue damage. C5aR, and the members of the FPR family that were previously thought to be restricted to phagocytes proved to have a much broader spectrum of cell expression. In addition to N-formylated peptides, numerous unrelated ligands were recently found to interact with FPR and FPRL1. Novel agonists include both pathogen- and host-derived components, and synthetic peptides. Antagonistic molecules have been identified that exhibit limited receptor specificity. How distinct ligands can both induce different biological responses and produce different modes of receptor activation and unique sets of cellular responses are discussed. Cell responses to chemoattractants are tightly regulated at the level of the receptors. This review describes in detail the regulation of receptor signalling and the multi-step process of receptor inactivation. New concepts, such as receptor oligomerization and receptor clustering, are considered. Although FPR, FPRL1 and C5aR trigger similar biological functions and undergo a rapid chemoattractant-mediated phosphorylation, they appear to be differentially regulated and experience different intracellular fates.

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“…11 C5a induces pro-inflammatory and cardiodepressant cytokines in human leucocytes including tumour necrosis factor-α, interleukin (IL)-1, IL-6, and IL-8. 12,13 Furthermore, the C5aR pathway regulates the expression of adhesion molecules on peripheral monocytes, as well as infiltration and cytokine production of macrophages in the heart. 4,9,14 Thus, C3a and C5a are important inflammatory mediators but might also be of pathophysiological relevance for cardiac tissue remodelling.…”

Section: Introductionmentioning

confidence: 99%

Myocardial expression of the anaphylatoxin receptor C3aR is associated with cardiac inflammation and prognosis in patients with non‐ischaemic heart failure

et al. 2018

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AimThe aim of this study is to analyse the prognostic value of complement anaphylatoxin receptors in patients with non‐ischaemic cardiomyopathy undergoing endomyocardial biopsy.Methods and resultsIn 102 patients (72.5% male patients, median age 54 years) with non‐ischaemic cardiomyopathy, myocardial expression of C3aR was assessed among other parameters. The primary study endpoint was a composite of death, heart transplantation, heart failure‐related re‐hospitalization, and deterioration of left ventricular ejection fraction within a mean follow‐up of 11.9 months. The number of cells, which stained positive for C3aR, was significantly increased in patients with inflammatory compared with non‐inflammatory cardiomyopathy (1.75 ± 0.31 cells in inflammatory cardiomyopathy vs. 0.94 ± 0.26 in non‐inflammatory cardiomyopathy, P = 0.049). Subsequently, positive expression for C3aR was judged based on a semi‐quantitative scoring system. Significantly, more patients with positive MHCII and CD68 expression showed an increased number of C3aR‐positive cells. C3aR expression based on this score was more pronounced in patients with human herpesvirus 6 viral genome detection. Kaplan–Meier curves illustrate that the C3aR‐negative group reached the primary endpoint significantly more often (mean follow‐up 11.9 months, log rank 5.963, P = 0.015). Lack of C3aR expression was a strong independent predictor for the primary endpoint in Cox regression analysis [hazard ratio 0.46 (0.26–0.82, P = 0.009)].ConclusionsC3aR‐positive cells are found more often in patients with inflammatory cardiomyopathy. The relevance of C3aR‐positive cells in patients with non‐ischaemic cardiomyopathy should be further evaluated as potential predictors or modulators of adverse cardiac remodelling, the substrate of progressive heart failure.

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INCREASED C5a RECEPTOR EXPRESSION IN SEPSIS.

Cited by 22 publications

References 13 publications

Neutrophil C5a receptor and the outcome in a rat model of sepsis

Neutrophil C5a receptor and the outcome in a rat model of sepsis

The N-formyl peptide receptors and the anaphylatoxin C5a receptors: An overview

Myocardial expression of the anaphylatoxin receptor C3aR is associated with cardiac inflammation and prognosis in patients with non‐ischaemic heart failure

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