Annexin A2 Enhances complement activation by inhibiting factor H

Brandon Renner, Hua Hua Tong, Jennifer Laskowski, Karen Jonscher, Lindsey Goetz, Rachel Woolaver, Jonathan Hannan, Yong Xing Li, Dennis Hourcade, Matthew C. Pickering, V. Michael Holers, Joshua M. Thurman

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1355-1365
Number of pages11
JournalJournal of Immunology
Volume196
Issue number3
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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