TLR activation enhances C5a-induced pro-inflammatory responses by negatively modulating the second C5a receptor, C5L2

Eur J Immunol. 2011 Sep;41(9):2741-52. doi: 10.1002/eji.201041350. Epub 2011 Aug 4.

Abstract

TLR and complement activation ensures efficient clearance of infection. Previous studies documented synergism between TLRs and the receptor for the pro-inflammatory complement peptide C5a (C5aR/CD88), and regulation of TLR-induced pro-inflammatory responses by C5aR, suggesting crosstalk between TLRs and C5aR. However, it is unclear whether and how TLRs modulate C5a-induced pro-inflammatory responses. We demonstrate a marked positive modulatory effect of TLR activation on cell sensitivity to C5a in vitro and ex vivo and identify an underlying mechanistic target. Pre-exposure of PBMCs and whole blood to diverse TLR ligands or bacteria enhanced C5a-induced pro-inflammatory responses. This effect was not observed in TLR4 signalling-deficient mice. TLR-induced hypersensitivity to C5a did not result from C5aR upregulation or modulation of C5a-induced Ca(2+) mobilization. Rather, TLRs targeted another C5a receptor, C5L2 (acting as a negative modulator of C5aR), by reducing C5L2 activity. TLR-induced hypersensitivity to C5a was mimicked by blocking C5L2 and was not observed in C5L2KO mice. Furthermore, TLR activation inhibited C5L2 expression upon C5a stimulation. These findings identify a novel pathway of crosstalk within the innate immune system that amplifies innate host defense at the TLR-complement interface. Unravelling the mutually regulated activities of TLRs and complement may reveal new therapeutic avenues to control inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Blocking / pharmacology
  • Calcium Signaling / immunology
  • Cells, Cultured
  • Complement C5a / immunology
  • Complement C5a / metabolism*
  • Feedback, Physiological
  • Humans
  • Immunity, Innate / drug effects
  • Immunity, Innate / genetics
  • Interleukin-8 / metabolism
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism*
  • Leukocytes, Mononuclear / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Knockout
  • Receptor Cross-Talk / immunology
  • Receptor, Anaphylatoxin C5a
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / immunology
  • Receptors, Chemokine / metabolism*
  • Receptors, Complement / immunology
  • Receptors, Complement / metabolism*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Antibodies, Blocking
  • C5AR1 protein, human
  • C5aR2 protein, human
  • Interleukin-8
  • Receptor, Anaphylatoxin C5a
  • Receptors, Chemokine
  • Receptors, Complement
  • Toll-Like Receptor 4
  • Complement C5a