Changes in the Novel Orphan, C5a Receptor (C5L2), during Experimental Sepsis and Sepsis in Humans

Huber‐Lang, Markus; Sarma, J. Vidya; Rittirsch, Daniel; Schreiber, Heike; Weiß, Manfred; Flierl, Michael A.; Younkin, Ellen M.; Schneider, Marion; Suger-Wiedeck, Heidemarie; Gebhard, Florian; McClintock, Shannon D.; Neff, Thomas; Zetoune, Firas S.; Brückner, U. B.; Guo, Ruocheng; Monk, Peter N.; Ward, Peter A.

doi:10.4049/jimmunol.174.2.1104

Cited by 73 publications

(66 citation statements)

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“…Moreover, C5L2 −/− mice show marginal improvement of survival in Escherichia coliinduced sepsis [29]. In contrast, the expression levels of C5L2 are reduced in neutrophils from rats and humans with progressive sepsis, which is associated with poor prognosis [30]. Thus, the functional roles of C5L2 have still been controversial in sepsis [31].…”

Section: Discussionmentioning

confidence: 98%

IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils

Kim

Ahn

et al. 2014

Eur J Immunol

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A role for NKT cells has been implicated in sepsis, but the mechanism by which NKT cells contribute to sepsis remains unclear. Here, we examined WT and NKT-cell-deficient mice of C57BL/6 background during cecal ligation and puncture-induced sepsis. The levels of C5a, IFN-γ, and IL-10 were higher in the serum and peritoneal fluid of WT mice than in those of CD1d −/− mice, while the mortality rate was lower in CD1d −/− mice than in WT mice. C5a blockade decreased mortality of WT mice during sepsis, whereas it did not alter that of CD1d −/− mice. As assessed by intracellular staining, NKT cells expressed IFN-γ, while neutrophils expressed IL-10. Upon coculture, IL-10-deficient NKT cells enhanced IL-10 production by WT, but not IFN-γR-deficient, neutrophils. Meanwhile, CD1d −/− mice exhibited high CD55 expression on neutrophils during sepsis, whereas those cells from WT mice expressed minimal levels of CD55. Recombinant IL-10 administration into CD1d −/− mice reduced CD55 expression on neutrophils. Furthermore, adoptive transfer of sorted WT, but not IFN-γ-deficient, NKT cells into CD1d −/− mice suppressed CD55 expression on neutrophils, but increased IL-10 and C5a levels. Taken together, IFN-γ-producing NKT cells enhance C5a generation via IL-10-mediated inhibition of CD55 expression on neutrophils, thereby exacerbating sepsis.Keywords: C5a r IFN-γ r Neutrophils r NKT cell r Sepsis Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNKT cells are a distinct T-cell subset characterized by the expression of natural killer receptors and semi-invariant TCRs. These cells recognize glycolipids presented by CD1d, an MHC class I-like Correspondence: Dr. Doo Hyun Chung e-mail: doohyun@snu.ac.kr protein expressed by APCs [1]. During bacterial infection, TCRs on NKT cells directly recognize glycolipids derived from certain Gramnegative bacterial membranes [2,3] and can be activated by innate cytokines secreted by dendritic cells that have been activated by microorganisms [2,4]. Furthermore, LPS-mediated engagement of TLR4 directly activates NKT cells in terms of differential * These authors contributed equally to this work. Eur. J. Immunol. 2014Immunol. . 44: 2025Immunol. -2035 cytokine production, thereby regulating immune diseases [5]. These findings suggest that NKT cells, activated during immune responses against bacteria, regulate bacteria-mediated pathologic processes such as sepsis. Sepsis is a complex inflammatory dysregulation that causes multiple organ dysfunction and coagulopathy, often resulting in death [6,7]. Several studies have demonstrated that NKT cells promote LPS-or cecal ligation and puncture (CLP)-induced sepsis in mice through the production of . Consistent with these findings, two independent studies have demonstrated that treatment of C57BL/6 mice with anti-CD1d antibody enhances survival rates during CLP-induced sepsis [11,12], suggesting that NKT-cell-mediated promotion of sepsis depends on an interaction between CD1d and TCR...

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Section: Discussionmentioning

confidence: 98%

IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils

Kim

Ahn

et al. 2014

Eur J Immunol

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“…[9][10][11][12] ). Furthermore, in human sepsis, C5L2 is downregulated on the surfaces of PMNs, the extent of which correlates with the harmful outcomes of sepsis 15 .…”

Section: Discussionmentioning

confidence: 99%

“…After washing of the 'buffy coat', we incubated PBMCs (3.5 × 10 6 cells/ml) with recombinant human C5A (50 nM; R&D Systems) for 12 × h at 37 °C in OPTI-MEM I. We isolated human PMNs as described elsewhere 15 and incubated them (5 × 10 6 cells/ml) for 5 h under the same conditions described above. As indicated in Figure 5, we pre-exposed PMNs and PBMCs to monoclonal antibodies to human C5AR 19 or C5L2 (1 μg/ml) or to A8 Δ71-73 (350 nM) 1 h before C5A exposure (50 nM) 17 .…”

Section: In Vitro Incubation Of Phagocytic Cellsmentioning

confidence: 99%

“…Like C5ar, C5l2 is abundantly expressed on both myeloid and nonmyeloid cells 14 . Loss of C5l2 on blood neutrophils during sepsis correlates with lethality 15 . Ina mouse model of acute lung injury, the use of Gpr77 -/-mice resulted in enhanced tissue injury, supporting the hypothesis that C5l2 may function as a modulating receptor for C5a and may therefore be anti-inflammatory 11 .…”

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Functional roles for C5a receptors in sepsis

Rittirsch

Flierl

Nadeau

et al. 2008

Nat Med

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The function of the C5a receptors, C5ar (encoded by C5ar) and C5l2 (encoded by Gpr77), especially of C5l2, which was originally termed a 'default receptor', remains a controversial topic. Here we investigated the role of each receptor in the setting of cecal ligation and puncture-induced sepsis by using antibody-induced blockade of C5a receptors and knockout mice. In 'mid-grade' sepsis (30-40% survival), blockade or absence of either C5ar or C5l2 greatly improved survival and attenuated the buildup of proinflammatory mediators in plasma. In vivo appearance or in vitro release of high mobility group box 1 protein (HMGB1) required C5l2 but not C5ar. In 'high-grade' sepsis (100% lethality), the only protective condition was the combined blockade of C5l2 and C5ar. These data suggest that C5ar and C5l2 contribute synergistically to the harmful consequences in sepsis and that C5l2 is required for the release of HMGB1. Thus, contrary to earlier speculation, C5l2 is a functional receptor rather than merely a default receptor.The complement anaphylatoxin, C5a, is generated during experimental sepsis and has been shown to play adverse roles in survival after cecal ligation and puncture (CLP) 1 16 . In the current work, we describe evidence for the combined roles of C5ar and C5l2 in the harmful outcomes of CLP-induced sepsis, including lethality and the surge of proinflammatory mediators in plasma. These data suggest that both C5ar and C5l2 cooperatively play functional parts in the setting of sepsis and that the role of C5l2 is specifically linked to the release of HMGB1, a known key mediator in CLP-induced lethality. RESULTS Specificity of antibodies to C5a receptorsUsing flow cytometry, we evaluated rabbit polyclonal antibodies to the N-terminal peptide regions of C5ar and C5l2. Antibody to C5ar bound to surfaces of blood neutrophils (PMNs) from wild-type mice (Fig. 1a). When the immunogenic peptide used to raise the antibody to C5ar was added, binding of IgG to PMNs was completely blocked (Fig. 1a). Addition of the C5l2 immunogenic peptide to the C5ar-specific antiserum did not alter the binding of IgG to C5ar (Fig. 1a). Likewise, C5l2-specific antiserum showed binding of IgG to blood PMNs (Fig. 1b). Addition of the immunogenic peptide for C5l2 abolished the IgG binding ( Fig. 1b), whereas addition of irrelevant peptide (immunogenic peptide for C5ar) did not affect binding (Fig. 1b). These data define the specificities of the antibodies to C5ar and C5l2.In order to address the concern that the absence of C5l2 might be associated with reduced expression of C5ar, we assessed the amount of C5ar on PMNs from either wild-type (Gpr77 +/+ ) or Gpr77 -/-mice (Fig. 1c). No quantitative difference in C5ar content was noted on the surface of PMNs from the two groups of mice. Accordingly, when PMNs from C5ar1 -/-and wild-type (C5ar1 +/+ ) mice were stained with the antibody to C5l2, C5ar1 -/-cells had similar expression of C5l2 on their surfaces as compared to cells from wild-type mice (Fig. 1d). These results suggest th...

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“…Generally, C5aR and C5L2 are independent, and the putative 'default' receptor, C5L2, has an important role in balancing the biological effects of C5a. 6 However, the role of C5L2 in inflammatory responses is controversial, 7,8 its elucidation will require further investigation. In sepsis, it has been reported that excessive systemic C5a levels were associated with exhaustion of the granulocytic response.…”

Section: Introductionmentioning

confidence: 99%

Complement 5a receptor-mediated neutrophil dysfunction is associated with a poor outcome in sepsis

Lin

Bao

et al. 2015

Cell Mol Immunol

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Changes in the Novel Orphan, C5a Receptor (C5L2), during Experimental Sepsis and Sepsis in Humans

Cited by 73 publications

References 48 publications

IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils

IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils

Functional roles for C5a receptors in sepsis

Complement 5a receptor-mediated neutrophil dysfunction is associated with a poor outcome in sepsis

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