title: Complement factor H binding of monomeric C-reactive protein downregulates proinflammatory activity and is impaired with at risk polymorphic CFH variants.
abstract: Inflammation and immune-mediated processes are pivotal to the pathogenic progression of age-related macular degeneration (AMD). Although plasma levels of C-reactive protein (CRP) have been shown to be associated with an increased risk for AMD, the pathophysiological importance of the prototypical acute-phase reactant in the etiology of the disease is unknown, and data regarding the exact role of CRP in ocular inflammation are limited. In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the "risk" His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained.
authors.affiliation: Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, 08028 Barcelona, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Molins
authors.affiliation: Molecular Bases of Disease, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08025 Barcelona, Spain.|Universitat Autònoma de Barcelona, 08193 Bellaterra (Cerdanyola del Vallès), Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Fuentes-Prior
authors.affiliation: Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, 08028 Barcelona, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Adán
authors.affiliation: Molecular Bases of Disease, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08025 Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Antón
authors.affiliation: Department of Immunology-CDB, Hospital Clínic-IDIBAPS, 08028 Barcelona, Spain.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Arostegui
authors.affiliation: Department of Immunology-CDB, Hospital Clínic-IDIBAPS, 08028 Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Yagüe
authors.affiliation: Academic Unit of Ophthalmology, School of Clinical Sciences and School of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TH, UK.|National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, EC1V 2PD, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Dick
mesh_terms: D000368:Aged; D002097:C-Reactive Protein / Q000378:metabolism*; D002460:Cell Line; D002634:Chemotaxis, Leukocyte; D017242:Complement Factor H / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008297:Male; D011110:Polymorphism, Genetic; D011485:Protein Binding; D055503:Protein Multimerization; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D057135:Wet Macular Degeneration / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D016209:Interleukin-8; D017242:Complement Factor H; D002097:C-Reactive Protein