Complement C5a induces pro-inflammatory microvesicle shedding in severely injured patients

peer-reviewed
Erstveröffentlichung
2020-09-02Authors
Karasu, Ebru
Demmelmaier, Julia
Kellermann, Stephanie
Holzmann, Karlheinz
Köhl, Jörg
Wissenschaftlicher Artikel
Published in
Frontiers in Immunology ; 11 (2020). - Art.-Nr. 1789. - eISSN 1664-3224
Link to original publication
https://dx.doi.org/10.3389/fimmu.2020.01789Faculties
Medizinische FakultätInstitutions
UKU. Institut für Klinische und Experimentelle Trauma-ImmunologieCore Facility Genomics
UKU. Institut für Naturheilkunde und Klinische Pharmakologie
Sonderforschungsbereich 1149 „Gefahrenantwort, Störfaktoren und regeneratives Potential nach akutem Trauma“
External cooperations
Universität zu LübeckCINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER
Document version
published version (publisher's PDF)Abstract
Initially underestimated as platelet dust, extracellular vesicles are continuously gaining
interest in the field of inflammation. Various studies addressing inflammatory diseases
have shown that microvesicles (MVs) originating from different cell types are systemic
transport vehicles carrying distinct cargoes to modulate immune responses. In this
study, we focused on the clinical setting of multiple trauma, which is characterized by
activation and dysfunction of both, the fluid-phase and the cellular component of innate
immunity. Given the sensitivity of neutrophils for the complement anaphylatoxin C5a,
we hypothesized that increased C5a production induces alterations in MV shedding
of neutrophils resulting in neutrophil dysfunction that fuels posttraumatic inflammation.
In a mono-centered prospective clinical study with polytraumatized patients, we found
significantly increased granulocyte-derived MVs containing the C5a receptor (C5aR1,
CD88) on their surface. This finding was accompanied by a concomitant loss of C5aR1
on granulocytes indicative of an impaired cellular chemotactic and pro-inflammatory
neutrophil functions. Furthermore, in vitro exposure of human neutrophils (from healthy
volunteers) to C5a significantly increased MV shedding and C5aR1 loss on neutrophils,
which could be blocked using the C5aR1 antagonist PMX53. Mechanistic analyses
revealed that the interaction between C5aR1 signaling and the small GTPase Arf6 acts
as a molecular switch for MV shedding. When neutrophil derived, C5a-induced MV
were exposed to a complex ex vivo whole blood model significant pro-inflammatory
properties (NADPH activity, ROS and MPO generation) of the MVs became evident.
C5a-induced MVs activated resting neutrophils and significantly induced IL-6 secretion.
These data suggest a novel role of the C5a-C5aR1 axis: C5a-induced MV shedding
from neutrophils results in decreased C5aR1 surface expression on the one hand, on
the other hand it leads to profound inflammatory signals which likely are both key drivers
of the neutrophil dysfunction which is regularly observed in patients suffering frommultiple
traumatic injuries.
Publication funding
Gefördert vom Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg
Open-Access-Förderung durch die Medizinische Fakultät der Universität Ulm
Open-Access-Förderung durch die Medizinische Fakultät der Universität Ulm
Is supplemented by
https://www.frontiersin.org/articles/10.3389/fimmu.2020.01789/full#supplementary-materialSubject headings
[GND]: Trauma | Neutrophiler Granulozyt[MeSH]: Multiple trauma | Neutrophils
[Free subject headings]: Microvesicle shedding | anaphylatoxin C5a | C5aR1 | neutrophils | Polymorphonuclear neutrophils (PMNs)
[DDC subject group]: DDC 610 / Medicine & health
Metadata
Show full item recordDOI & citation
Please use this identifier to cite or link to this item: http://dx.doi.org/10.18725/OPARU-34000
Karasu, Ebru et al. (2020): Complement C5a induces pro-inflammatory microvesicle shedding in severely injured patients. Open Access Repositorium der Universität Ulm und Technischen Hochschule Ulm. http://dx.doi.org/10.18725/OPARU-34000
Citation formatter >