Dataset Information

Recombinant TSP1 cleaved by HTRA1 (LCMS)

ABSTRACT: HTRA1 proteolysis of TSP1 inhibits immune suppression in age-related macular degeneration. A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age related macular degeneration (AMD), a major cause of blindness affecting millions of individuals worldwide. Here we show that monocytes (Mo) from homozygous carriers of the 10q26 AMD-risk haplotype overexpress the High-Temperature Requirement A Serine Peptidase 1 (HTRA1), which locates to mononuclear phagocytes (MP) in eyes of patients with AMD. Elevated HTRA1 led to significant subretinal Mo persistence and promoted pathogenic MP accumulation due to the hydrolysis of Thrombospondin 1 (TSP1). Mechanistically, we demonstrate that HTRA1 separates TSP1’s two CD47- binding Valine-Valine-Methionine-sites that are necessary for efficient CD47 activation and repression of osteopontin (OPN) secretion, a mediator of inflammation and wound healing. Accordingly, OPN was overexpressed in early Mo-derived macrophages in 10q26 risk carriers and OPN deletion or inhibition fully reversed HTRA1- induced pathogenic MP persistence. Our observations provide new insights into the molecular mechanisms of MP accumulation in inflammation and show that HTRA1 resistant CD47 agonists and OPN inhibitors can provide a powerful tool to reverse HTRA1’s pro-inflammatory effect and restore retinal immune suppression in AMD, critical for retinal homeostasis.

INSTRUMENT(S): HCTultra

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Age Related Macular Degeneration

SUBMITTER: Solenne Chardonnet

LAB HEAD: Solenne Chardonnet

PROVIDER: PXD020546 | Pride | 2020-07-25

REPOSITORIES: Pride

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Publications

The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination.

Beguier Fanny F Housset Michael M Roubeix Christophe C Augustin Sebastien S Zagar Yvrick Y Nous Caroline C Mathis Thibaud T Eandi Chiara C Benchaboune Mustapha M Drame-Maigné Adèle A Carpentier Wassila W Chardonnet Solenne S Touhami Sara S Blot Guillaume G Conart Jean Baptiste JB Charles-Messance Hugo H Potey Anaïs A Girmens Jean-François JF Paques Michel M Blond Fréderic F Leveillard Thierry T Koertvely Elod E Roger Jerome E JE Sahel José-Alain JA Sapieha Przemyslaw P Delarasse Cécile C Guillonneau Xavier X Sennlaub Florian F

Immunity 20200801 2

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 inflam ...[more]

PMID: 32814029

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Project description:Background Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. Recent studies have demonstrated strong genetic associations between AMD and single nucleotide polymorphisms (SNPs) within genes such as CFH and HTRA1. However, we have identified monozygotic twins discordant for AMD phenotypes (one with disease, the other without disease), suggesting that an epigenetic mechanism may also contribute to the pathogenesis of AMD. Methods We identified two twin pairs with phenotypic discordance of AMD. We obtained genomic DNA from their peripheral blood mononuclear cells (PBMCs) and subjected them to DNA methylation-chip analysis (MeDIP-chip) that profiled genome-wide DNA methylation patterns on promoters of all genes and microRNAs. We next utilized the Methyl-Profiler DNA methylation assays to detect the methylation status of selected promoters. Flow cytometry and quantitative real-time PCR were used to detect the expression of the selected gene in peripheral blood cells, as well as in retinal and choroidal tissues of AMD patients and non-AMD controls. Results Our MeDIP-chip analysis identified 256 genes with hypo-methylated promoters only in the twins with AMD and 744 genes with hyper-methylated promoters only in the twins with AMD. Importantly, the promoter region of IL17RC was associated with hypo-methylated CpG sites only in the twins with AMD but not in the twins without AMD. We also found the association of the hypo-methylated IL17RC promoter with AMD in 7 pairs of siblings with discordant AMD pathology (P=0.003), as well as an independent patient cohort (95 neovascular wet and 107 geographic atrophy dry AMD patients as well as 96 non-AMD controls (95% CI, 0.01-0.10, P=9.8x10-8 for wet AMD vs. control; 95% CI, 0.05-0.32, P=2.2x10-5 for dry AMD vs. control)). Interestingly, we did not find an association between the levels of methylation on the IL17RC promoter with the previously identified genetic risk alleles in CFH, HTRA1, and ARMS2. We demonstrated an elevated expression of the IL-17RC protein in CD14+ monocytes in the peripheral blood of AMD patients as compared to non-AMD controls. These IL-17RC+ monocytes have elevated expression of CXCR1, CXCR2, and CXCR4. In addition, IL17RC was expressed only in the retinal and choroidal tissues from AMD patients but not from age-matched controls. Conclusions We show an association of the hypo-methylated IL17RC promoter with AMD, which resulted in the elevated expression of IL-17RC in peripheral blood cells as well as the retinal and choroidal tissues of AMD patients. Our study suggests that the hypo-methylated IL17RC promoter and elevated expression of IL-17RC can potentially serve as biomarkers for the diagnosis of AMD, while IL-17RC can be a new therapeutic target for AMD. In addition, our results strongly suggest an epigenetic control mechanism of AMD pathogenesis. The Affymetrix MOE430 2.0 GeneChip was used to detect gene expression patterns within the whole eye of C57B/6 normal mice.

Dataset Information

Recombinant TSP1 cleaved by HTRA1 (LCMS)

Publications

The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination.

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