C5L2: a controversial receptor of complement anaphylatoxin, C5a

Li, Rui; Coulthard, Liam G.; Wu, Mike C. L.; Taylor, Stephen M.; Woodruff, Trent M.

doi:10.1096/fj.12-220509

Cited by 181 publications

(168 citation statements)

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“…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]. Nevertheless, it is demonstrated that NKT cells minimally express C5L2 after E. coli infection, whereas these cells show high expression of C5aR [29].…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…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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“…After its generation, C3a is cleaved quickly at the C-terminal arginine to form C3a-desArg. This molecule has no detectable activity at C3aR, but it was shown by some groups to bind the second receptor for C5a, C5aR2 (C5L2) (17,18). The interactions with C5aR2 exhibit effects on metabolism and, in this sphere, C3a-desArg is homologous to acetylation-stimulating protein (19).…”

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Is the Complement Activation Product C3a a Proinflammatory Molecule? Re-evaluating the Evidence and the Myth

Coulthard

Woodruff

2015

The Journal of Immunology

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The complement activation product C3a is often described as a proinflammatory mediator, alongside its downstream cousin, C5a. However, emerging studies show that C3a has several anti-inflammatory facets in vivo. For example, in the acute inflammatory response, C3a acts in direct opposition to C5a, through preventing the accumulation of neutrophils in inflamed tissues by independently regulating their mobilization. This acute, protective, and opposing activity of C3a to C5a is also illustrated in models of septicemia. In this article, we reinvestigate the discovery and original classification of C3a as a proinflammatory mediator and highlight the emerging studies demonstrating anti-inflammatory effects for C3a in the immune response. It is our hope that this review illuminates these apparently contradictory roles for C3a and challenges the general dogma surrounding C3a, which, historically, has ubiquitously been described as a proinflammatory mediator. In light of this, we urge investigators to use “inflammatory modulator” as the descriptor for C3a.

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C5L2: a controversial receptor of complement anaphylatoxin, C5a

Cited by 181 publications

References 57 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

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

Is the Complement Activation Product C3a a Proinflammatory Molecule? Re-evaluating the Evidence and the Myth

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