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Complement C5a induces PD-L1 expression and acts in synergy with LPS through Erk1/2 and JNK signaling pathways
Author(s) -
Ling–Ling An,
Jacob V. Gorman,
Geoffrey L. Stephens,
Bonnie Swerdlow,
Paul Warrener,
Jessica Bonnell,
Tomas Mustelin,
Michael Fung,
Roland Kolbeck
Publication year - 2016
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep33346
Subject(s) - immune system , complement system , inflammation , c5a receptor , signal transduction , alternative complement pathway , complement receptor , immunology , pseudomonas aeruginosa , biology , classical complement pathway , complement membrane attack complex , microbiology and biotechnology , bacteria , genetics
Severe bacterial infection results in both uncontrolled inflammation and immune suppression in septic patients. Although there is ample evidence that complement activation provokes overwhelming pro-inflammatory responses, whether or not it plays a role in immune suppression in this case is unclear. Here, we identify that complement C5a directly participates in negative regulation of immune responses to bacteria-induced inflammation in an ex vivo model of human whole blood. Challenge of whole blood with heat-killed Pseudomonas aeruginosa induces PD-L1 expression on monocytes and the production of IL-10 and TGF-β, which we show to be inhibited by C5a blockade. The induction of PD-L1 expression by C5a is via C5aR1but not C5aR2. Furthermore, C5a synergises with P. aeruginosa LPS in both PD-L1 expression and the production of IL-10 and TGF-β. Mechanistically, C5a contributes to the synergy in PD-L1 expression by specifically activating Erk1/2 and JNK signaling pathways. Our study reveals a new role for C5a in directly promoting immunosuppressive responses. Therefore, aberrant production of complement C5a during bacterial infection could have broader effect on compromising host defense including the induction of immune suppression.

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