Complement C5a induces PD-L1 expression and acts in synergy with LPS through Erk1/2 and JNK signaling pathways.
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.
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, LLC. One Medimmune Way, Gaithersburg, MD 20878, USA.
Ling-Ling
LL
An
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, LLC. One Medimmune Way, Gaithersburg, MD 20878, USA.
Jacob V
JV
Gorman
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, LLC. One Medimmune Way, Gaithersburg, MD 20878, USA.
Geoffrey
G
Stephens
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, LLC. One Medimmune Way, Gaithersburg, MD 20878, USA.
Bonnie
B
Swerdlow
Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, MD 20878, USA.
Paul
P
Warrener
Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, MD 20878, USA.
Jessica
J
Bonnell
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, LLC. One Medimmune Way, Gaithersburg, MD 20878, USA.
Tomas
T
Mustelin
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, LLC. One Medimmune Way, Gaithersburg, MD 20878, USA.
Michael
M
Fung
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, LLC. One Medimmune Way, Gaithersburg, MD 20878, USA.
Roland
R
Kolbeck
D060890:B7-H1 Antigen / Q000378:metabolism*; D015936:Complement C5a / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D011550:Pseudomonas aeruginosa / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D060890:B7-H1 Antigen; C423236:CD274 protein, human; D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015936:Complement C5a; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases