| Autor: |
Croker DE; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia., Halai R; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia., Kaeslin G; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia., Wende E; Department of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany., Fehlhaber B; Department of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany., Klos A; Department of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany., Monk PN; Department of Infection and Immunity, University of Sheffield Medical School, Sheffield, UK., Cooper MA; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. |
| Abstrakt: |
The complement system is a major component of our innate immune system, in which the complement proteins C5a and C5a-des Arg bind to two G-protein-coupled receptors: namely, the C5a receptor (C5a1) and C5a receptor like-2 receptor (C5a2, formerly called C5L2). Recently, it has been demonstrated that C5a, but not C5a-des Arg, upregulates heteromer formation between C5a1 and C5a2, leading to an increase in IL-10 release from human monocyte-derived macrophages (HMDMs). A bioluminescence resonance energy transfer (BRET) assay was used to assess the recruitment of β-arrestins by C5a and C5a-des Arg at the C5a1 and C5a2 receptors. C5a demonstrated elevated β-arrestin 2 recruitment levels in comparison with C5a-des Arg, whereas no significant difference was observed at C5a2. A constitutive complex that formed between β-arrestin 2 and C5a2 accounted for half of the BRET signal observed. Interestingly, both C5a and C5a-des Arg exhibited higher potency for β-arrestin 2 recruitment via C5a2, indicating preference for C5a2 over C5a1. When C5a was tested in a functional ERK1/2 assay in HMDMs, inhibition of ERK1/2 was observed only at concentrations at or above the EC50 for heteromer formation. This suggested that increased recruitment of the β-arrestin-C5a2 complex at these C5a concentrations might have an inhibitory role on C5a1 signaling through ERK1/2. An improved understanding of C5a2 modulation of signaling in acute inflammation could be of benefit in the development of ligands for conditions such as sepsis. |
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