C5L2 Is a Functional Receptor for Acylation-stimulating Protein

Kalant, David; MacLaren, Robin; Cui, Wei; Samanta, Ratna; Monk, Peter N.; Laporte, Stéphane A.; Cianflone, Katherine

doi:10.1074/jbc.m406921200

Cited by 165 publications

(199 citation statements)

References 52 publications

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“…However, we observed a trend of CCL2 and C3 induction after C3a-desArg stimulation. Recently, another functional receptor of C3a and C3a-desArg, named C5L2, has been described (44). However, we could not detect C5L2 expression on unstimulated KCs and KCs stimulated with variety of cytokines.…”

Section: Discussioncontrasting

confidence: 47%

Induction of C3 and CCL2 by C3a in Keratinocytes: A Novel Autocrine Amplification Loop of Inflammatory Skin Reactions

Purwar

Wittmann

Zwirner

et al. 2006

The Journal of Immunology

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The complement fragment-3a (C3a) acts via a G protein-coupled C3aR and is of importance in allergic and inflammatory diseases. Recent studies suggest the presence of complement proteins in the epidermal compartment and synthesis of some of these proteins (C3, factor B, and factor H) by human primary keratinocytes (KCs) during inflammation. However, expression of C3aR and its role in human KCs is not elucidated thus far. In this study, we demonstrate the expression of C3aR on KCs as detected by quantitative real-time RT-PCR and flow cytometry. IFN-γ and IFN-α strongly up-regulated the surface expression of C3aR on KCs among all other cytokines tested. After up-regulation of C3aR by IFN-γ and IFN-α, we observed the induction of five genes (CCL2, CCL5, CXCL8, CXCL10, and C3) after stimulation of KCs with C3a in microarray analysis. We confirmed the induction of C3 and CCL2 at RNA and protein levels. Furthermore, incubation of C3 with skin mast cells tryptase resulted in the generation of C3 fragments with C3a activity. In conclusion, our data illustrate that epidermal KCs express functional C3aR. The increases of C3 and CCL2 synthesis by C3a and C3 activation by skin mast cell tryptase delineates a novel amplification loop of complement activation and inflammatory responses that may influence the pathogenesis of allergic/inflammatory skin diseases.

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Section: Discussioncontrasting

confidence: 47%

Induction of C3 and CCL2 by C3a in Keratinocytes: A Novel Autocrine Amplification Loop of Inflammatory Skin Reactions

Purwar

Wittmann

Zwirner

et al. 2006

The Journal of Immunology

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“…One way in which C5l2 differs from C5ar is in the so-called DRY region of the third intracellular loop (replacement of arginine by leucine), resulting in an uncoupling of C5l2 from G protein interactions 6,7 . Binding of C5a (and C5a desArg ) to C5l2 does not result in increased intracellular calcium, although recent evidence suggests that there may be activation of MAPKs in phagocytes and that interaction of C3a desArg with C5l2 might be associated with protein acylation and triglyceride synthesis in adipocytes [6][7][8]13 . It was hypothesized that C5l2 may function as a default or modulating receptor for C5a, competing with C5ar for binding of C5a 11,18,21 .…”

Section: Discussionmentioning

confidence: 99%

“…In addition to C5ar, C5l2 represents a second high affinity receptor for C5a and C5a desArg . There is still controversy about the expression of C5l2, its ligands and its functional role in biological responses [4][5][6][7][8]13 . One way in which C5l2 differs from C5ar is in the so-called DRY region of the third intracellular loop (replacement of arginine by leucine), resulting in an uncoupling of C5l2 from G protein interactions 6,7 .…”

Section: Discussionmentioning

confidence: 99%

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Functional roles for C5a receptors in sepsis

Rittirsch

Flierl

Nadeau

et al. 2008

Nat Med

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363

425

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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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“…CFB is produced by adipose tissue where they likely influence the production of the anaphylatoxin C3a and its carboxypeptidase B-anaphylatoxic-inactivated derivative C3adesArg (ASP). Both ASP/C3adesArg and C3a interact with the receptor C5L2 to effectively stimulate triglyceride synthesis in cultured adipocytes (39). C3 knockout (C3KO) mice are obligatorily ASP deficient and show lipid abnormalities (40).…”

Section: Discussionmentioning

confidence: 99%

Circulating glucagon is associated with inflammatory mediators in metabolically compromised subjects

Ortega¹,

Moreno-Navarrete²,

Sabater³

et al. 2011

European Journal of Endocrinology

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Background: Acute phase mediators promote metabolic changes by modifying circulating hormones. However, there is virtually no data about the link between glucagon and inflammatory parameters in obesity-related chronic low-grade inflammation. Study design: We performed both cross-sectional and longitudinal (diet-induced weight loss) studies. Methods: Circulating glucagon concentrations (ELISA), parameters of glucose and lipid metabolism, interleukin 6 (IL6), and complement factor B (CFB) were analyzed in 316 subjects (250 men and 66 women). The effects of weight loss were investigated in an independent cohort of 20 subjects. Results: Circulating glucagon significantly correlated with glucose (rZ0.407, P!0.0001), HbAlc (rZ0.426, P!0.0001), fasting triglycerides (rZ0.356, PZ0.001), and parameters of innate immune response system such as IL6 (rZ0.342, PZ0.050) and CFB (rZ0.404, PZ0.002) in obese subjects with altered glucose tolerance, but not in individuals with normal glucose tolerance (NGT). In obese and NGT subjects, glucagon was associated with fasting triglycerides (rZ0.475, PZ0.003) and CFB (rZ0.624, PZ0.001). In obese subjects, glucagon (PZ0.019) and CFB (PZ0.002) independently contributed to 26% of fasting triglyceride variance (P!0.0001) after controlling for the effects of age and fasting serum glucose concentration in multiple lineal regression models. Moreover, concomitant with fat mass, fasting triglycerides, and CFB, weight loss led to significantly decreased circulating glucagon (K23.1%, PZ0.004). Conclusions: According to the current results, acute phase reactants such as IL6 and CFB are associated with fasting glucagon in metabolically compromised subjects. This suggests that glucagon may be behind the association between inflammatory and metabolic parameters in obesity-associated chronic low-grade inflammation.

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C5L2 Is a Functional Receptor for Acylation-stimulating Protein

Cited by 165 publications

References 52 publications

Induction of C3 and CCL2 by C3a in Keratinocytes: A Novel Autocrine Amplification Loop of Inflammatory Skin Reactions

Induction of C3 and CCL2 by C3a in Keratinocytes: A Novel Autocrine Amplification Loop of Inflammatory Skin Reactions

Functional roles for C5a receptors in sepsis

Circulating glucagon is associated with inflammatory mediators in metabolically compromised subjects

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