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Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections
Please always quote using this URN: urn:nbn:de:bvb:20-opus-200496
- 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 nasalThe 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.…
Author: | Marcel Muenstermann, Lea Strobel, Andreas Klos, Rick A. Wetsel, Trent M. Woodruff, Jörg Köhl, Kay O. JohswichORCiD |
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URN: | urn:nbn:de:bvb:20-opus-200496 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Institut für Hygiene und Mikrobiologie |
Language: | English |
Parent Title (English): | Virulence |
Year of Completion: | 2019 |
Volume: | 10 |
Issue: | 1 |
Pagenumber: | 677-694 |
Source: | Virulence 2019, Vol. 10, No. 1, 677-694. DOI: 10.1080/21505594.2019.1640035 |
DOI: | https://doi.org/10.1080/21505594.2019.1640035 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | C3a; C3aR; C5a; C5aR1; C5aR2; inflammation; meningococcal disease; sepsis |
Release Date: | 2020/03/30 |
Collections: | Open-Access-Publikationsfonds / Förderzeitraum 2019 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |