Complement C3a, CpG Oligos, and DNA/C3a Complex Stimulate IFN-α Production in a Receptor for Advanced Glycation End Product-Dependent Manner

Ruan, Benfang; Li, Xin; Winkler, Aaron; Cunningham, Kristina; Kuai, Jun; Greco, Rita; Nocka, Karl; Fitz, Lori; Wright, Jill F.; Pittman, Debra D.; Tan, Xiang-Yang; Paulsen, Janet; Lin, Lih Ling; Winkler, David G.

doi:10.4049/jimmunol.1000863

Cited by 71 publications

(46 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Second, RAGE expression is upregulated in the kidneys of SLE patients (23), and signaling through HMGB1-RAGE activates mesangial cells in vitro, therefore suggesting a role for the RAGE axis in the progression of lupus nephritis (24). Furthermore, other alarmin molecules such as C3a as well as CpG DNA oligos are able to bind to RAGE and stimulate IFN-a production by human PBMCs in a RAGE-dependent manner (25,26).…”

Section: Discussionmentioning

confidence: 99%

Deletion of Receptor for Advanced Glycation End Products Exacerbates Lymphoproliferative Syndrome and Lupus Nephritis in B6-MRL Fas lpr/j Mice

Goury

Meghraoui-Kheddar

Belmokhtar

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that interacts with advanced glycation end products, but also with C3a, CpG DNA oligonucleotides, and alarmin molecules such as HMGB1 to initiate a proinflammatory reaction. Systemic lupus erythematosus is an autoimmune disorder associated with the accumulation of RAGE ligands. We generated mice invalidated for RAGE in the lupus-prone B6-MRL Fas lpr/j background to determine the role of RAGE in the pathogenesis of systemic lupus erythematosus. We compared the phenotype of these mice with that of their wild-type and B6-MRL Fas lpr/j littermates. Lymphoproliferative syndrome, production of anti-dsDNA Abs, lupus nephritis, and accumulation of CD3+B220+CD4−CD8− autoreactive T cells (in the peripheral blood and the spleen) were significantly increased in B6-MRL Fas lpr/j RAGE−/− mice compared with B6-MRL Fas lpr/j mice (respectively p < 0.005, p < 0.05, p < 0.001, and p < 0.001). A large proportion of autoreactive T cells from B6-MRL Fas lpr/j mice expressed RAGE at their surface. Time course studies of annexin V expression revealed that autoreactive T cells in the spleen of B6-MRL Fas lpr/j-RAGE−/− mice exhibited a delay in apoptosis and expressed significantly less activated caspase 3 (39.5 ± 4.3%) than T cells in B6-MRL Fas lpr/j mice (65.5 ± 5.2%) or wild-type mice (75.3 ± 2.64%) (p = 0.02). We conclude that the deletion of RAGE in B6-MRL Fas lpr/j mice promotes the accumulation of autoreactive CD3+B220+CD4−CD8− T cells, therefore exacerbating lymphoproliferative syndrome, autoimmunity, and organ injury. This suggests that RAGE rescues the apoptosis of T lymphocytes when the death receptor Fas/CD95 is dysfunctional.

show abstract

Section: Discussionmentioning

confidence: 99%

Deletion of Receptor for Advanced Glycation End Products Exacerbates Lymphoproliferative Syndrome and Lupus Nephritis in B6-MRL Fas lpr/j Mice

Goury

Meghraoui-Kheddar

Belmokhtar

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…C3a was also shown to bind to the receptor for advanced glycosylation end-products (RAGE) with a high affinity, but this interaction is more complex than a simple ligand-receptor interaction (29,30). Ruan et al (29) demonstrated that C3a is able to form a complex with CpG oligonucleotides to enhance IFN-a release from mononuclear leukocytes.…”

mentioning

confidence: 99%

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

Coulthard

Woodruff

2015

The Journal of Immunology

251

200

View full text Add to dashboard Cite

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.

show abstract

“…The syndrome has also been linked to increased risk of developing preeclampsia and other pregnancy complications such as IUGR and fetal loss 89,90 . In mouse models, complement has been shown to be pivotal to the pregnancy complications associated with APS, as inhibition of C3 cleavage, through the use of C3-deficient animals of C3 convertase inhibitors, can prevent the growth restriction and fetal loss 87,91,92 .…”

Section: C1qmentioning

confidence: 99%

“…However, although the pharmacology of SB290157 may be controversial, the conclusion drawn by the authors may now be reinterpreted to take into account the acute 'anti-neutrophil' effects of C3aR discovered recently 47 . It is uncontroversial that, at least at the level of the nephron, C3aR is involved in the pathogenesis of renal disease, including the induction of metaplasia in nephron epithelial cells central to the disease 91,92 . These actions appear synergistic to the role of C5aR1 at the tissue level, but may be redundant in the presence of 69 elevated C5a concentrations, which is much more potent than C3a as a pro-inflammatory mediator at the receptor level.…”

Section: (Iii) Renal Diseasementioning

confidence: 99%

See 1 more Smart Citation

The anaphylatoxin receptors in neural progenitor physiology

Coulthard¹

View full text Add to dashboard Cite

The complement cascade is phylogenically ancient pathogen recognition and response system that forms the initial frontier of mammalian innate immunity. Complement forms the bridge between humoural and cellular immunity through the generation of the anaphylatoxins, C3a and C5a, to recruit leukocytes to a pathogenic insult. However, in recent years, novel roles for the complement system outside of innate immunity have been demonstrated, especially in the developing embryo.To add to these novel roles, this thesis explores the role of the complement anaphylatoxin receptors in neural development.Previous studies in our laboratory have indicated a novel role for C5aR1 in the prevention of neural tube defects in folate-deficient dams. In these studies, C5aR1 was localised to the neuroepithelium throughout the period of neural tube closure and the precursor to C5a, C5, was also shown to be present. It has previously been unclear, both in this study and others, what other components of the complement system are present in the developing embryo that may lead to the generation ofanaphylatoxins. Here we demonstrate that the classical and alternative pathways, at the time of murine neural tube closure, lack expression of key propagators. Our data demonstrate the C2/4-independent and extrinsic pathways remain patent as a plausible means of C5a generation.In order to trace C5aR1-expressing cells within the developing embryo, a transgenic mouse was

show abstract

Complement C3a, CpG Oligos, and DNA/C3a Complex Stimulate IFN-α Production in a Receptor for Advanced Glycation End Product-Dependent Manner

Cited by 71 publications

References 41 publications

Deletion of Receptor for Advanced Glycation End Products Exacerbates Lymphoproliferative Syndrome and Lupus Nephritis in B6-MRL Fas lpr/j Mice

Deletion of Receptor for Advanced Glycation End Products Exacerbates Lymphoproliferative Syndrome and Lupus Nephritis in B6-MRL Fas lpr/j Mice

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

The anaphylatoxin receptors in neural progenitor physiology

Contact Info

Product

Resources

About