Universität zu Köln

Micklisch, Sven, Lin, Yuchen, Jacob, Saskia, Karlstetter, Marcus, Dannhausen, Katharina, Dasari, Prasad, von der Heide, Monika, Dahse, Hans-Martin, Schmoelz, Lisa, Grassmann, Felix ORCID: 0000-0003-1390-7528, Alene, Medhanie, Fauser, Sascha, Neumann, Harald ORCID: 0000-0002-5071-5202, Lorkowski, Stefan ORCID: 0000-0002-9649-840X, Pauly, Diana, Weber, Bernhard H., Joussen, Antonia M., Langmann, Thomas, Zipfel, Peter F. and Skerka, Christine (2017). Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator. J. Neuroinflamm., 14. LONDON: BIOMED CENTRAL LTD. ISSN 1742-2094

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Abstract

Background: Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. The polymorphism rs10490924 in the ARMS2 gene is highly associated with AMD and linked to an indel mutation (del443ins54), the latter inducing mRNA instability. At present, the function of the ARMS2 protein, the exact cellular sources in the retina and the biological consequences of the rs10490924 polymorphism are unclear. Methods: Recombinant ARMS2 was expressed in Pichia pastoris, and protein functions were studied regarding cell surface binding and complement activation in human serum using fluoresence-activated cell sorting (FACS) as well as laser scanning microscopy (LSM). Biolayer interferometry defined protein interactions. Furthermore, endogenous ARMS2 gene expression was studied in human blood derived monocytes and in human induced pluripotent stem cell-derived microglia (iPSdM) by PCR and LSM. The ARMS2 protein was localized in human genotyped retinal sections and in purified monocytes derived from AMD patients without the ARMS2 risk variant by LSM. ARMS2 expression in monocytes under oxidative stress was determined by Western blot analysis. Results: Here, we demonstrate for the first time that ARMS2 functions as surface complement regulator. Recombinant ARMS2 binds to human apoptotic and necrotic cells and initiates complement activation by recruiting the complement activator properdin. ARMS2-properdin complexes augment C3b surface opsonization for phagocytosis. We also demonstrate for the first time expression of ARMS2 in human monocytes especially under oxidative stress and in microglia cells of the human retina. The ARMS2 protein is absent in monocytes and also in microglia cells, derived from patients homozygous for the ARMS2 AMD risk variant (rs10490924). Conclusions: ARMS2 is likely involved in complement-mediated clearance of cellular debris. As AMD patients present with accumulated proteins and lipids on Bruch's membrane, ARMS2 protein deficiency due to the genetic risk variant might be involved in drusen formation.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Micklisch, Sven UNSPECIFIED UNSPECIFIED UNSPECIFIED Lin, Yuchen UNSPECIFIED UNSPECIFIED UNSPECIFIED Jacob, Saskia UNSPECIFIED UNSPECIFIED UNSPECIFIED Karlstetter, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Dannhausen, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Dasari, Prasad UNSPECIFIED UNSPECIFIED UNSPECIFIED von der Heide, Monika UNSPECIFIED UNSPECIFIED UNSPECIFIED Dahse, Hans-Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmoelz, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Grassmann, Felix UNSPECIFIED orcid.org/0000-0003-1390-7528 UNSPECIFIED Alene, Medhanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Fauser, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED Neumann, Harald UNSPECIFIED orcid.org/0000-0002-5071-5202 UNSPECIFIED Lorkowski, Stefan UNSPECIFIED orcid.org/0000-0002-9649-840X UNSPECIFIED Pauly, Diana UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Bernhard H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Joussen, Antonia M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Langmann, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Zipfel, Peter F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Skerka, Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-242777
DOI:	10.1186/s12974-016-0776-3
Journal or Publication Title:	J. Neuroinflamm.
Volume:	14
Date:	2017
Publisher:	BIOMED CENTRAL LTD
Place of Publication:	LONDON
ISSN:	1742-2094
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language APOPTOTIC CELLS; PROPERDIN BINDS; MESSENGER-RNA; HIGH-RISK; VARIANT; RARE; EXPRESSION; REGULATORS; DISEASE; CONFERS Multiple languages Immunology; Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24277