Abstract
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.
Highlights
Anaphylatoxin C5a generated from uncontrolled complement activation has been associated with inflammatory “cytokine storm” in sepsis patients[1,2]
Since PD-L1 can be induced on primary monocytes[15], which express C5aR1 and C5aR2, we investigated whether C5a could be directly involved in PD-L1 dependent immune suppression during the acute inflammation
We examined the direct effect of complement C5a on the modulation of PD-L1 expression and the production of IL-10 and TGF-βafter human whole blood was challenged with heat-killed gram negative bacteria, P. aeruginosa
Summary
C5a induces PD-L1 expression and the production of IL-10 and TGF-β. To determine the direct effect of complement C5a on immune suppression in ex vivo, we challenged freshly collected human whole blood with heat-killed P. aeruginosa, a highly relevant opportunistic pathogen in sepsis. Combination of C5a and LPS synergistically increased PD-L1 expression, IL-10 and TGF-βproduction (Fig. 2B–D), implying that C5aR1 and TLR2 likely acted through distinct but interactive pathways These data are in agreement with early findings that C5aR1 and TLR2 or TLR4 synergized in inducing immune suppression, where cAMP was generated from macrophages in a P. gingivalis infection model[27] and production of IL-6 and TNF-αwas inhibited in human monocyte-derived macrophages[28]. Blocking C5a together with TLR2 completely abolished PD-L1 expression on monocytes in fresh human blood challenged with heat-killed P. aeruginosa Both C5a and LPS activate p38 MAPK and NF-κB signaling pathways, C5a alone activates Erk1/2 and JNK signaling pathways to induce PD-L1 expression. These data suggest that in addition to pro-inflammatory responses, C5a plays an important role in generating immunosuppressive responses during the acute phase of gram negative bacteria-induced inflammation
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