Factor H–Related Protein 5 Interacts with Pentraxin 3 and the Extracellular Matrix and Modulates Complement Activation

Journal of Immunology - Tập 194 Số 10 - Trang 4963-4973 - 2015
Ádám I. Csincsi1, Anne Kopp2, Miklós Zöldi1, Zsófia Bánlaki1, Barbara Uzonyi3, Mario Hebecker2, Joseph J. E. Caesar4, Matthew C. Pickering5, Kenji Daigo6, Takao Hamakubo6, Susan M. Lea4, Elena Goicoechea de Jorge5, Mihály Józsi1,2
1*Hungarian Academy of Sciences–Eötvös Loránd University “Lendület” Complement Research Group, Department of Immunology, Eötvös Loránd University, 1117 Budapest, Hungary;
2†Junior Research Group for Cellular Immunobiology, Leibniz Institute for Natural Product Research and Infection Biology–Hans Knöll Institute, 07745 Jena, Germany;
3‡Hungarian Academy of Sciences–Eötvös Loránd University Immunology Research Group, Department of Immunology, Eötvös Loránd University, 1117 Budapest, Hungary;
4§Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RF, United Kingdom;
5¶Centre for Complement and Inflammation Research, Department of Medicine, Imperial College, London W12 0NN, United Kingdom; and
6Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan

Tóm tắt

AbstractThe physiological roles of the factor H (FH)-related proteins are controversial and poorly understood. Based on genetic studies, FH-related protein 5 (CFHR5) is implicated in glomerular diseases, such as atypical hemolytic uremic syndrome, dense deposit disease, and CFHR5 nephropathy. CFHR5 was also identified in glomerular immune deposits at the protein level. For CFHR5, weak complement regulatory activity and competition for C3b binding with the plasma complement inhibitor FH have been reported, but its function remains elusive. In this study, we identify pentraxin 3 (PTX3) as a novel ligand of CFHR5. Binding of native CFHR5 to PTX3 was detected in human plasma and the interaction was characterized using recombinant proteins. The binding of PTX3 to CFHR5 is of ∼2-fold higher affinity compared with that of FH. CFHR5 dose-dependently inhibited FH binding to PTX3 and also to the monomeric, denatured form of the short pentraxin C–reactive protein. Binding of PTX3 to CFHR5 resulted in increased C1q binding. Additionally, CFHR5 bound to extracellular matrix in vitro in a dose-dependent manner and competed with FH for binding. Altogether, CFHR5 reduced FH binding and its cofactor activity on pentraxins and the extracellular matrix, while at the same time allowed for enhanced C1q binding. Furthermore, CFHR5 allowed formation of the alternative pathway C3 convertase and supported complement activation. Thus, CFHR5 may locally enhance complement activation via interference with the complement-inhibiting function of FH, by enhancement of C1q binding, and by activating complement, thereby contributing to glomerular disease.

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Journal of Immunology

Tập 194 Số 10

4963-4973

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