Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections

Abstract

The complement system is pivotal in the defense against invasive disease caused by Neisseria meningitidis (Nme, meningococcus), particularly via the membrane attack complex. Complement activation liberates the anaphylatoxins C3a and C5a, which activate three distinct G-protein coupled receptors, C3aR, C5aR1 and C5aR2 (anaphylatoxin receptors, ATRs). We recently discovered that C5aR1 exacerbates the course of the disease, revealing a downside of complement in Nme sepsis. Here, we compared the roles of all three ATRs during mouse nasal colonization, intraperitoneal infection and human whole blood infection with Nme. Deficiency of complement or ATRs did not alter nasal colonization, but significantly affected invasive disease: Compared to WT mice, the disease was aggravated in C3ar −/mice, whereas C5ar1 −/and C5ar2 −/mice showed increased resistance to meningococcal sepsis. Surprisingly, deletion of either of the ATRs resulted in lower cytokine/chemokine responses, irrespective of the different susceptibilities of the mice. This was similar in ex vivo human whole blood infection using ATR inhibitors. Neutrophil responses to Nme were reduced in C5ar1 −/mouse blood. Upon stimulation with C5a plus Nme, mouse macrophages displayed reduced phosphorylation of ERK1/2, when C5aR1 or C5aR2 were ablated or inhibited, suggesting that both C5a-receptors prime an initial macrophage response to Nme. Finally, in vivo blockade of C5aR1 alone (PMX205) or along with C5aR2 (A8 Δ71−73) resulted in ameliorated disease, whereas neither antagonizing C3aR (SB290157) nor its activation with a "super-agonist" peptide (WWGKKYRASKLGLAR) demonstrated a benefit. Thus, C5aR1 and C5aR2 augment disease pathology and are interesting targets for treatment, whereas C3aR is protective in experimental meningococcal sepsis.

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

“…To overcome this safety burden, direct inhibition of C5a or C5aR1 would allow for anti-inflammatory activity in diseases mediated by the anaphylatoxin without compromising MAC formation. In addition, inhibition of the C5a–C5aR1 axis has been found to alleviate Neisseria -induced sepsis in mice ( 190 ). Moreover, C5a generated through direct C5 cleavage by proteases other than C5 convertase can be neutralized with agents directly targeting the C5a-C5aR1 axis ( 191 ).…”

Role of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock

“…6 and 7). The singular and combined effects of C5aR1 and C5aR2 have been elucidated in a range of biological responses [44][45][46] . Mice deficient in C5aR1 or C5aR2 were used in this regard to distinguish between their effects, because NoxD21 practically blocks the www.nature.com/scientificreports/ activity of both these receptors concomitantly.…”

Complement in sepsis—when science meets clinics

“…Another study in LPS-induced shock with systemic inflammation demonstrated an early enhanced lethality rate of C3aR-deficient mice, but after a 72-h observation period, no changes could be detected between the wild-type and C3aR-deficient littermates [32]. In experimental meningococcal sepsis, a differential role for the C3aR and the C5a receptors has recently been reported: whereas C5aR1 and C5aR2 aggravated the disease immune pathology, C3aR was rather protective [33]. Thus, C3a seems to reveal some protective effects, possibly by activating the hypothalamus-pituitary-adrenal axis and by inhibition of neuronal cell death [32].…”