TY - JOUR
T1 - Complement regulation at necrotic cell lesions is impaired by the age-related macular degeneration-associated factor-H His402 risk
AU - Lauer, Variant Nadine
AU - Mihlan, Michael
AU - Hartmann, Andrea
AU - Schlötzer-Schrehardt, Ursula
AU - Keilhauer, Claudia
AU - Scholl, Hendrik P.N.
AU - Issa, Peter Charbel
AU - Holz, Frank
AU - Weber, Bernhard H.F.
AU - Skerka, Christine
AU - Zipfel, Peter F.
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2011/10/15
Y1 - 2011/10/15
N2 - Age-related macular degeneration is a leading form of blindness in Western countries and is associated with a common SNP (rs 1061170/Y402H) in the Factor H gene, which encodes the two complement inhibitors Factor H and FHL1. However, the functional consequences of this Tyr402 His exchange in domain 7 are not precisely defined. In this study, we show that the Tyr402 His sequence variation affects Factor H surface recruitment by monomeric C-reactive protein (mCRP) to specific patches on the surface of necrotic retinal pigment epithelial cells. Enhanced attachment of the protective Tyr402 variants of both Factor H and FHL1 by mCRP results in more efficient complement control and further provides an anti-inflammatory environment. In addition, we demonstrate that mCRP is generated on the surface of necrotic retinal pigment epithelial cells and that this newly formed mCRP colocalizes with the cell damage marker annexin V. Bound to the cell surface, Factor H-mCRP complexes allow complement inactivation and reduce the release of the proinflammatory cytokine TNF-α. This mCRP-mediated complement inhibitory and anti-inflammatory activity at necrotic membrane lesions is affected by residue 402 of Factor H and defines a new role for mCRP, for Factor H, and also for the mCRP-Factor H complex. The increased protective capacity of the Tyr 402 Factor H variant allows better and more efficient clearance and removal of cellular debris and reduces inflammation and pathology.
AB - Age-related macular degeneration is a leading form of blindness in Western countries and is associated with a common SNP (rs 1061170/Y402H) in the Factor H gene, which encodes the two complement inhibitors Factor H and FHL1. However, the functional consequences of this Tyr402 His exchange in domain 7 are not precisely defined. In this study, we show that the Tyr402 His sequence variation affects Factor H surface recruitment by monomeric C-reactive protein (mCRP) to specific patches on the surface of necrotic retinal pigment epithelial cells. Enhanced attachment of the protective Tyr402 variants of both Factor H and FHL1 by mCRP results in more efficient complement control and further provides an anti-inflammatory environment. In addition, we demonstrate that mCRP is generated on the surface of necrotic retinal pigment epithelial cells and that this newly formed mCRP colocalizes with the cell damage marker annexin V. Bound to the cell surface, Factor H-mCRP complexes allow complement inactivation and reduce the release of the proinflammatory cytokine TNF-α. This mCRP-mediated complement inhibitory and anti-inflammatory activity at necrotic membrane lesions is affected by residue 402 of Factor H and defines a new role for mCRP, for Factor H, and also for the mCRP-Factor H complex. The increased protective capacity of the Tyr 402 Factor H variant allows better and more efficient clearance and removal of cellular debris and reduces inflammation and pathology.
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U2 - 10.4049/jimmunol.1002488
DO - 10.4049/jimmunol.1002488
M3 - Article
C2 - 21930971
AN - SCOPUS:80054742530
SN - 0022-1767
VL - 187
SP - 4374
EP - 4383
JO - Journal of Immunology
JF - Journal of Immunology
IS - 8
ER -