title: Annexin A2 Enhances Complement Activation by Inhibiting Factor H.
abstract: Factor H is a circulating protein that regulates activation of the alternative pathway (AP) of complement. Mutations and genetic variations of factor H are associated with several AP-mediated diseases, highlighting the critical role of factor H in AP regulation. AP-mediated inflammation is typically triggered by illness or tissue injury, however, and tissue injury can trigger AP activation in individuals with fully functional factor H. This suggests that factor H function is affected by local conditions within tissues. We hypothesized that inducible proteins impair the ability of factor H to locally control the AP, thereby increasing AP activation. We used purified murine factor H to immunoprecipitate binding partners from mouse kidneys. Using immunoaffinity liquid chromatography-mass spectrometry, we identified annexin A2 as a factor H binding partner. Further experiments showed that annexin A2 reduces the binding of factor H to cell surfaces. Recombinant annexin A2 impaired complement regulation by factor H and increased complement activation on renal cell surfaces in vitro and in vivo. In a murine model of acute pneumococcal otitis media, the administration of annexin A2 increased AP-mediated bacterial opsonization and clearance. In conclusion, the local production of annexin A2 within tissues suppresses regulation of the AP by factor H. Annexin A2 can contribute to AP-mediated tissue inflammation by locally impairing factor H function, but it can also improve complement-mediated bacterial clearance.
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Brandon
authors.identifier: http://orcid.org/0000-0002-6060-4119
authors.initials: B
authors.lastname: Renner
authors.affiliation: Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210;
authors.forename: Hua Hua
authors.identifier: http://orcid.org/0000-0001-7758-3687
authors.initials: HH
authors.lastname: Tong
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Jennifer
authors.identifier: http://orcid.org/0000-0001-5069-3982
authors.initials: J
authors.lastname: Laskowski
authors.affiliation: Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Karen
authors.identifier: http://orcid.org/0000-0002-7929-4886
authors.initials: K
authors.lastname: Jonscher
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Lindsey
authors.identifier: http://orcid.org/0000-0003-1554-2569
authors.initials: L
authors.lastname: Goetz
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Rachel
authors.identifier: http://orcid.org/0000-0003-1960-2717
authors.initials: R
authors.lastname: Woolaver
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Jonathan
authors.identifier: http://orcid.org/0000-0003-3318-2341
authors.initials: J
authors.lastname: Hannan
authors.affiliation: Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210;
authors.forename: Yong Xing
authors.identifier: http://orcid.org/0000-0001-8983-2820
authors.initials: YX
authors.lastname: Li
authors.affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and.
authors.forename: Dennis
authors.initials: D
authors.lastname: Hourcade
authors.affiliation: Centre for Complement and Inflammation Research, South Kensington Campus, Imperial College, London SW7 2AZ, United Kingdom.
authors.forename: Matthew C
authors.identifier: http://orcid.org/0000-0002-1153-0192
authors.initials: MC
authors.lastname: Pickering
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; Joshua.Thurman@ucdenver.edu.
authors.forename: Joshua M
authors.identifier: http://orcid.org/0000-0002-3476-9956
authors.initials: JM
authors.lastname: Thurman
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology; D000818:Animals; D017306:Annexin A2 / Q000276:immunology*; D015153:Blotting, Western; D002853:Chromatography, Liquid; D003167:Complement Activation / Q000276:immunology*; D017242:Complement Factor H / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D010033:Otitis Media / Q000276:immunology; D015427:Reperfusion Injury / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017306:Annexin A2; D017242:Complement Factor H