TY - JOUR
T1 - Annexin A2 Enhances complement activation by inhibiting factor H
AU - Renner, Brandon
AU - Tong, Hua Hua
AU - Laskowski, Jennifer
AU - Jonscher, Karen
AU - Goetz, Lindsey
AU - Woolaver, Rachel
AU - Hannan, Jonathan
AU - Li, Yong Xing
AU - Hourcade, Dennis
AU - Pickering, Matthew C.
AU - Michael Holers, V.
AU - Thurman, Joshua M.
N1 - Publisher Copyright:
© 2016 by The American Association of Immunologists, Inc.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84957642167&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1500793
DO - 10.4049/jimmunol.1500793
M3 - Article
C2 - 26729803
AN - SCOPUS:84957642167
SN - 0022-1767
VL - 196
SP - 1355
EP - 1365
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -