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Florian Sennlaub, MD, PhD - "How genetic-risk variants of age–related macular degeneration shape pathogenic inflammation"

Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
When Apr 09, 2019
from 12:00 PM to 01:30 PM
Where Tigem, Vesuvius Auditorium
Contact Name
Contact Phone 081-19230659
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Abstract
CD47 activation by Thrombospondin 1 (TSP-1) is essential in maintaining the subretinal immunosuppressive environment and prevents the subretinal accumulation of macrophages. Age-related Macular Degeneration (AMD), a highly heritable, major cause of blindness, is characterized by the breakdown of the immune-suppression and an accumulation of pathogenic MPs. Of all genetic factors, a variant of Complement factor H (CFH) and a risk haplotype of 10q26 are associated with greatest linkage to AMD. We recently showed that complement factor H (CFH) and in particular the AMD-associated CFH variant, curbs Thrombospondin 1 (TSP-1) activation of CD47. We now demonstrate that monocytes from homozygous carriers of the major AMD-risk haplotype of the 10q26 locus significantly overexpress the High-Temperature Requirement A Serine Peptidase 1 (HTRA1). Mechanistically we demonstrate that HTRA1 hydrolyses TSP-1, preventing its ability to activate CD47 and induce MP elimination. Our study reveals a comprehensive mechanism how CFH and HTRA1 participate in the pathogenesis of AMD and opens new therapeutic avenues to restore subretinal immunosuppressivity and inhibit the pathogenic subretinal inflammation.

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