title: TLR activation enhances C5a-induced pro-inflammatory responses by negatively modulating the second C5a receptor, C5L2.
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.
authors.affiliation: Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Raby
authors.forename: Benjamin
authors.initials: B
authors.lastname: Holst
authors.forename: James
authors.initials: J
authors.lastname: Davies
authors.forename: Chantal
authors.initials: C
authors.lastname: Colmont
authors.forename: Yves
authors.initials: Y
authors.lastname: Laumonnier
authors.forename: Barbara
authors.initials: B
authors.lastname: Coles
authors.forename: Sanjoy
authors.initials: S
authors.lastname: Shah
authors.forename: Judith
authors.initials: J
authors.lastname: Hall
authors.forename: Nicholas
authors.initials: N
authors.lastname: Topley
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
authors.forename: Mario O
authors.initials: MO
authors.lastname: Labéta
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D020013:Calcium Signaling / Q000276:immunology; D002478:Cells, Cultured; D015936:Complement C5a / Q000276:immunology / Q000378:metabolism*; D025461:Feedback, Physiological; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D016209:Interleukin-8 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D020239:Receptor Cross-Talk / Q000276:immunology; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011951:Receptors, Complement / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; C488033:C5AR1 protein, human; C417003:C5aR2 protein, human; D016209:Interleukin-8; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D011951:Receptors, Complement; D051197:Toll-Like Receptor 4; D015936:Complement C5a