Properdin binds to late apoptotic and necrotic cells independently of C3b and regulates alternative pathway complement activation.
Cells that undergo apoptosis or necrosis are promptly removed by phagocytes. Soluble opsonins such as complement can opsonize dying cells, thereby promoting their removal by phagocytes and modulating the immune response. The pivotal role of the complement system in the handling of dying cells has been demonstrated for the classical pathway (via C1q) and lectin pathway (via mannose-binding lectin and ficolin). Herein we report that the only known naturally occurring positive regulator of complement, properdin, binds predominantly to late apoptotic and necrotic cells, but not to early apoptotic cells. This binding occurs independently of C3b, which is additional to the standard model wherein properdin binds to preexisting clusters of C3b on targets and stabilizes the convertase C3bBb. By binding to late apoptotic or necrotic cells, properdin serves as a focal point for local amplification of alternative pathway complement activation. Furthermore, properdin exhibits a strong interaction with DNA that is exposed on the late stage of dying cells. Our data indicate that direct recognition of dying cells by properdin is essential to drive alternative pathway complement activation.
Xu
Wei
W
Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
Berger
Stefan P
SP
Trouw
Leendert A
LA
de Boer
Hetty C
HC
Schlagwein
Nicole
N
Mutsaers
Chantal
C
Daha
Mohamed R
MR
van Kooten
Cees
C
D017209:Apoptosis; D045744:Cell Line, Tumor; D015922:Complement C1q / Q000276:immunology / Q000378:metabolism; D051561:Complement C3 Convertase, Alternative Pathway; D003179:Complement C3b / Q000276:immunology / Q000378:metabolism*; D003170:Complement Pathway, Alternative; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology / Q000378:metabolism; D019169:Jurkat Cells; D009336:Necrosis; D010587:Phagocytosis; D011414:Properdin / Q000276:immunology / Q000378:metabolism*
D007155:Immunologic Factors; D011414:Properdin; D015922:Complement C1q; D003179:Complement C3b; D051561:Complement C3 Convertase, Alternative Pathway