Two different transduction pathways are activated by C3a and C5a anaphylatoxins on astrocytes

Sayah, S.; Jauneau, Anne-Christine; Patte, Christine; Tonon, Marie‐Christine; Vaudry, Hubert; Fontaine, Marc

doi:10.1016/s0169-328x(03)00046-9

Cited by 72 publications

(64 citation statements)

References 43 publications

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“…The activity of C3a in the bloodstream and tissues is tightly controlled by carboxypeptidases, which rapidly remove the Cterminal Arg residue (38,39). The resulting molecule, called C3a-desArg, is devoid of proinflammatory activity (40). We, therefore, believe that the C3a-like molecule generated by NalP, which lacks the C-terminal 4 aa, would also lack the biological functions observed by intact C3a.…”

Section: Discussionmentioning

confidence: 99%

Neisseria meningitidis NalP cleaves human complement C3, facilitating degradation of C3b and survival in human serum

Tordello

Vacca

Ram

et al. 2013

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

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The complement system is a crucial component of the innate immune response against invading bacterial pathogens. The human pathogen Neisseria meningitidis (Nm) is known to possess several mechanisms to evade the complement system, including binding to complement inhibitors. In this study, we describe an additional mechanism used by Nm to evade the complement system and survive in human blood. Using an isogenic NalP deletion mutant and NalP complementing strains, we show that the autotransporter protease NalP cleaves C3, the central component of the complement cascade. The cleavage occurs 4 aa upstream from the natural C3 cleavage site and produces shorter C3a-like and longer C3b-like fragments. The C3b-like fragment is degraded in the presence of the complement regulators (factors H and I), and this degradation results in lower deposition of C3b on the bacterial surface. We conclude that NalP is an important factor to increase the survival of Nm in human serum.serum resistance | immune evasion

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Section: Discussionmentioning

confidence: 99%

Neisseria meningitidis NalP cleaves human complement C3, facilitating degradation of C3b and survival in human serum

Tordello

Vacca

Ram

et al. 2013

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

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“…Previous studies have found that prostaglandins (I 2 and E 2 ) with anti-inflammatory properties, when binding to G␣ s protein-coupled receptors (PGI 2 receptor and PGE 2 receptor), increase intracellular cAMP levels and subsequently inhibit proinflammatory cytokine production in DCs (35)(36)(37). In contrast, C3a, as a potent inflammatory peptide, when stimulating DCs and astrocytes, decreases the level of intracellular cAMP (10,23). Consistent with the observation on C3a, in this study we found that the intracellular cAMP level in DCs decreased following C5a stimulation, suggesting that C5a may also exert its function through the G␣ i protein-coupled C5aR and lead to decreased levels of intracellular cAMP.…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cell Function in Allostimulation Is Modulated by C5aR Signaling

Peng

Wang

et al. 2009

The Journal of Immunology

106

103

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Regulation of T cell immunity by C5a has been suggested from recent studies. However, the underlying mechanisms, particularly the involved cells and biochemical basis, are not well defined. In this study, the direct modulation of dendritic cell (DC) activation and its function in T cell stimulation by C5a-C5aR interaction and the involved signaling pathways were investigated. We show that DCs from C5aR−/− mice and normal DCs treated with C5aR antagonist have less-activated phenotype characterized with increased IL-10 and decreased IL-12p70 production in response to LPS stimulation, lowered surface expression of MHC class II, B7.2, and consequently have reduced capacity to stimulate allospecific T cells. Conversely, C5a stimulation up-regulates DC activation and its function in allostimulation. Furthermore, stimulation of C5aR mediates the inhibition of cAMP production and protein kinase A activity and is involved in activation of PI3K/AKT and NF-κB signaling in DCs. These results demonstrate that C5a acts directly on C5aR expressed on DCs resulting in the cell activation and subsequently enhances its capacity for allospecific T cell stimulation. It also suggests that NF-κB signaling induced by down-regulation of cAMP/ protein kinase A pathway and up-regulation of PI3K/AKT pathway following C5a stimulation may contribute to up-regulation of DC function.

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“…C3aR is a classical seven-transmembrane, G proteincoupled receptor that shares close homology to the receptors for C5a, C5aR1, and C5aR2. C3aR couples to heterotrimeric G proteins and demonstrate a promiscuity of G protein interaction that is dependent on cell type (20)(21)(22). Intriguingly, the internalization and recycling of C3aR, which are dependent on G protein-coupled receptor kinase-mediated receptor phosphorylation (23), are inhibited by the presence of C5a in human granulocytes (24).…”

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

239

200

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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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Two different transduction pathways are activated by C3a and C5a anaphylatoxins on astrocytes

Cited by 72 publications

References 43 publications

Neisseria meningitidis NalP cleaves human complement C3, facilitating degradation of C3b and survival in human serum

Neisseria meningitidis NalP cleaves human complement C3, facilitating degradation of C3b and survival in human serum

Dendritic Cell Function in Allostimulation Is Modulated by C5aR Signaling

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

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