The team of Professor Florian Sennlaub from Sorbonne Université recently reported a mechanistic understanding of how a minor haplotype of 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD), indicating that CD47 agonists and OPN inhibitors can be a potential treatment of AMD.
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Title: The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination
Institution of the first author: Sorbonne Université, France
Institution of the corresponding author: Sorbonne Université, France
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A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Here, we examined the mechanisms underlying this susceptibility.
We found that monocytes from homozygous carriers of the 10q26 AMD-risk haplotype expressed high amounts of the serine peptidase HTRA1, and HTRA1 located to mononuclear phagocytes (MPs) in eyes of non-carriers with AMD.
HTRA1 induced the persistence of monocytes in the subretinal space and exacerbated pathogenic inflammation by hydrolyzing thrombospondin 1 (TSP1), which separated the two CD47-binding sites within TSP1 that are necessary for efficient CD47 activation. This HTRA1-induced inhibition of CD47 signaling induced the expression of pro-inflammatory osteopontin (OPN). OPN expression increased in early monocyte-derived macrophages in 10q26 risk carriers. In models of subretinal inflammation and AMD, OPN deletion or pharmacological inhibition reversed HTRA1-induced pathogenic MP persistence.
Our findings argue for the therapeutic potential of CD47 agonists and OPN inhibitors for the treatment of AMD.
1. 10q26 AMD-risk haplotype carrying monocytes overexpress HTRA1 and OPN.
2. HTRA1 locates to mononuclear phagocytes in eyes of patients with AMD.
3. HTRA1 proteolysis of TSP-1 curbs CD47-dependent OPN repression.
4. HTRA1 induced OPN promotes pathogenic subretinal MP accumulation.
5. The researchers indicated that CD47 agonists and OPN inhibitors can be a potential treatment of AMD.
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