title: Alternative pathway regulation by factor H modulates Streptococcus pneumoniae induced proinflammatory cytokine responses by decreasing C5a receptor crosstalk.
abstract: Bacterial pathogens not only stimulate innate immune receptors, but also activate the complement system. Crosstalk between complement C5a receptor (C5aR) and other innate immune receptors is known to enhance the proinflammatory cytokine response. An important determinant of the magnitude of complement activation is the activity of the alternative pathway, which serves as an amplification mechanism for complement activation. Both alternative pathway activity as well as plasma levels of factor H, a key inhibitor of the alternative pathway, show large variation within the human population. Here, we studied the effect of factor H-mediated regulation of the alternative pathway on bacterial-induced proinflammatory cytokine responses. We used the human pathogen Streptococcus pneumoniae as a model stimulus to induce proinflammatory cytokine responses in human peripheral blood mononuclear cells. Serum containing active complement enhanced pneumococcal induced proinflammatory cytokine production through C5a release and C5aR crosstalk. We found that inhibition of the alternative pathway by factor H, with a concentration equivalent to a high physiological level, strongly reduced C5a levels and decreased proinflammatory cytokine production in human peripheral blood mononuclear cells. This suggests that variation in alternative pathway activity due to variation in factor H plasma levels affects individual cytokine responses during infection.
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboudumc, 6525 GA Nijmegen, The Netherlands.
authors.forename: Erika
authors.initials: E
authors.lastname: van der Maten
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboudumc, 6525 GA Nijmegen, The Netherlands.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: de Bont
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboudumc, 6525 GA Nijmegen, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: de Groot
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboudumc, 6525 GA Nijmegen, The Netherlands.
authors.forename: Marien I
authors.initials: MI
authors.lastname: de Jonge
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboudumc, 6525 GA Nijmegen, The Netherlands.
authors.forename: Jeroen D
authors.initials: JD
authors.lastname: Langereis
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboudumc, 6525 GA Nijmegen, The Netherlands; Pediatric Infectious Diseases and Immunology, Department of Pediatrics, Radboudumc, 6525 GA Nijmegen, The Netherlands. Electronic address: michiel.vanderflier@radboudumc.nl.
authors.forename: Michiel
authors.initials: M
authors.lastname: van der Flier
mesh_terms: D000328:Adult; D017242:Complement Factor H / Q000276:immunology*; D003170:Complement Pathway, Alternative / Q000276:immunology*; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000276:immunology*
chemical_list: C488033:C5AR1 protein, human; D044087:Receptor, Anaphylatoxin C5a; D017242:Complement Factor H
keywords: Alternative pathway; C5aR crosstalk; Complement; Factor H; Proinflammatory cytokines; Streptococcus pneumoniae