Regulation by C5a of Neutrophil Activation during Sepsis

Riedemann, Niels C.; Guo, Ruocheng; Bernacki, Kurt D.; Reuben, Jayne S.; Laudes, Ines J.; Neff, Thomas; Gao, Hongwei; Speyer, Cecilia L.; Sarma, Vidya; Zetoune, Firas S.; Ward, Peter A.

doi:10.1016/s1074-7613(03)00206-1

Cited by 102 publications

(90 citation statements)

References 28 publications

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“…The consequences of combined signaling by C5a and UDP in macrophages may be particularly important in areas of inflammation, where C5a is produced, and where UDP may be released from dying cells (59). C5a in particular plays a central role in inflammation, and consequences of Ca 2ϩ signaling would be augmented by UDP, whereas consequences of PI3K activation would be inhibited.…”

Section: Discussionmentioning

confidence: 99%

Signaling and Cross-talk by C5a and UDP in Macrophages Selectively Use PLCβ3 to Regulate Intracellular Free Calcium

Roach

Rebres

Fraser

et al. 2008

Journal of Biological Chemistry

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Studies in fibroblasts, neurons, and platelets have demonstrated the integration of signals from different G proteincoupled receptors (GPCRs) in raising intracellular free Ca 2؉ . To study signal integration in macrophages, we screened RAW264.7 cells and bone marrow-derived macrophages (BMDM) for their Ca 2؉ response to GPCR ligands. We found a synergistic response to complement component 5a (C5a) in combination with uridine 5-diphosphate (UDP), platelet activating factor (PAF), or lysophosphatidic acid (LPA). The C5a response was G␣ i -dependent, whereas the UDP, PAF, and LPA responses were G␣ q -dependent. Synergy between C5a and UDP, mediated by the C5a and P2Y6 receptors, required dual receptor occupancy, and affected the initial release of Ca 2؉ from intracellular stores as well as sustained Ca 2؉ levels. C5a and UDP synergized in generating inositol 1,4,5-trisphosphate, suggesting synergy in activating phospholipase C (PLC) ␤. Macrophages expressed transcripts for three PLC␤ isoforms (PLC␤2, PLC␤3, and PLC␤4), but GPCR ligands selectively used these isoforms in Ca 2؉ signaling. C5a predominantly used PLC␤3, whereas UDP used PLC␤3 but also PLC␤4. Neither ligand required PLC␤2. Synergy between C5a and UDP likewise depended primarily on PLC␤3. Importantly, the Ca 2؉ signaling deficiency observed in PLC␤3-deficient BMDM was reversed by re-constitution with PLC␤3. Neither phosphatidylinositol (PI) 3-kinase nor protein kinase C was required for synergy. In contrast to Ca 2؉ , PI 3-kinase activation by C5a was inhibited by UDP, as was macropinocytosis, which depends on PI 3-kinase. PLC␤3 may thus provide a selective target for inhibiting Ca 2؉

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Section: Discussionmentioning

confidence: 99%

Signaling and Cross-talk by C5a and UDP in Macrophages Selectively Use PLCβ3 to Regulate Intracellular Free Calcium

Roach

Rebres

Fraser

et al. 2008

Journal of Biological Chemistry

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“…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).…”

Section: Discussionmentioning

confidence: 99%

C5a-Blockade Improves Burn-Induced Cardiac Dysfunction

Hoesel

Niederbichler²,

Schaefer

et al. 2007

The Journal of Immunology

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We previously reported that generation of the anaphylatoxin C5a is linked to the development of cardiac dysfunction in sepsis due to C5a interaction with its receptor (C5aR) on cardiomyocytes. Burn injury involves inflammatory mechanisms that can lead to C5a generation as well. In this study, we investigated the effects of C5a blockade on burn-induced cardiac dysfunction. Using a standardized rat model of full thickness scald injury, left ventricular pressures were recorded in vivo followed by in vitro assessment of sarcomere contraction of single cardiomyocytes. Left ventricular pressures in vivo and cardiomyocyte sarcomere contractility in vitro were significantly reduced following burn injury. In the presence of anti-C5a Ab, these defects were greatly attenuated 1, 6, and 12 h after burn injury and completely abolished 24 h after burn. In vitro incubation of cardiomyocytes with bacterial LPS accentuated the impaired contractility, which was partially prevented in cardiomyocytes from burned rats that had received an anti-C5a Ab. Based on Western blot analyses, real-time PCR, and immunostaining of left ventricular heart tissue, there was a significant increase in cardiomyocyte expression of C5aR after burn injury. In conclusion, an in vivo blockade of C5a attenuates burn-induced cardiac dysfunction. Further deterioration of contractility due to the exposure of cardiomyocytes to LPS was partially prevented by C5a-blockade. These results suggest a linkage between C5a and burn-induced cardiac dysfunction and a possible contribution of LPS to these events.

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“…Macrophage tolerance, a state of decreased responsiveness of inflammatory gene expression, has been shown to be associated with increased expression of the IB and IB genes (30). Recently, increased IB␣ expression has been linked to C5a-induced inhibition of lipopolysaccharide-dependent tumor necrosis factor ␣ production in neutrophils (31). Other studies have demonstrated decreased NF-B activation in response to increased levels of IB␣ induced by transforming growth factor ␤1 in human salivary gland cells (32).…”

Section: Discussionmentioning

confidence: 99%

Developmentally regulated IκB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation

Claud

Lü

Anton

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

203

145

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Necrotizing enterocolitis is a devastating inflammatory condition of the intestine that occurs almost exclusively in premature newborns. Although its exact pathogenesis is unclear, we have postulated that it may result from a predisposition of the immature intestine to mount an unusually robust and damaging response to microbial infection. In support of this idea, we report that the IL-8 response of an immature human enterocyte cell line to bacterial infection was significantly higher than that of a mature enterocyte cell line. The response in both cell lines was flagellin-dependent. Corresponding to the difference in IL-8 production, the immature enterocytes expressed appreciably lower levels of specific IB genes when compared with the mature enterocytes. Similar developmentally regulated differences in cytokine response and IB expression were also seen in primary rat enterocytes, indicating that these observations were not peculiarities of the cell lines. Furthermore, when the level of IB␣ expression was increased in the immature cell line by transfection, the flagellin-dependent IL-8 response was attenuated. Thus, we have demonstrated a previously undescribed developmental regulation of IB expression in the intestine involved in modulating the IL-8 response to bacterial infection, which may contribute to the pathogenesis of age-specific inflammatory bowel diseases such as necrotizing enterocolitis. E nterocytes are active participants in host defense against microbial invasion. Certain aspects of this function are developmentally regulated, resulting in distinct differences between the immature and mature intestine with respect to interactions with microorganisms (1-4). Immaturity of epithelial barrier function, relative deficiencies in the expression of antimicrobial factors, and developmental variations in the pattern of epithelial surface glycosylation all contribute to the susceptibility of early postnatal intestine to bacterial infection (5-7). Concurrently, the secretion of proinflammatory cytokines is greater at earlier stages of development than in the adult. Specifically, IL-8 production in response to IL-1␤ and tumor necrosis factor ␣ has been shown to be significantly increased in the human fetal intestinal epithelial cell (IEC) line H4 and fetal intestinal organ cultures compared with the adult IEC line Caco2 and biopsies from older children (8). The combination of weaker antimicrobial defense mechanisms and exaggerated cytokine responses may render the immature gut prone to extensive inflammatory damage after infection. These properties could thus contribute to the pathogenesis of age-specific diseases such as necrotizing enterocolitis (NEC), an ischemic and inflammatory bowel necrosis that primarily affects premature neonates after the initiation of enteral feeding.We have postulated a model of NEC pathogenesis in which early feeding results in exposure to numbers and types of bacteria that the premature intestine is ill-equipped to handle (9). The exaggerated inflammatory responses that are cha...

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Regulation by C5a of Neutrophil Activation during Sepsis

Cited by 102 publications

References 28 publications

Signaling and Cross-talk by C5a and UDP in Macrophages Selectively Use PLCβ3 to Regulate Intracellular Free Calcium

Signaling and Cross-talk by C5a and UDP in Macrophages Selectively Use PLCβ3 to Regulate Intracellular Free Calcium

C5a-Blockade Improves Burn-Induced Cardiac Dysfunction

Developmentally regulated IκB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation

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