4.8 Article

Mast cell infiltration of the choroid and protease release are early events in age-related macular degeneration associated with genetic risk at both chromosomes 1q32 and 10q26

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NATL ACAD SCIENCES
DOI: 10.1073/pnas.2118510119

关键词

age-related macular degeneration; proteomics; mast cells

资金

  1. Fight for Sight UK [1517/18]
  2. Macular Society (United Kingdom)
  3. Medical Research Council UK [MR/N028457/1]
  4. Biotechnology and Biological Sciences Research Council (United Kingdom)
  5. Wellcome Trust (United Kingdom)
  6. University of Manchester Strategic Fund

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Age-related macular degeneration (AMD) is a major cause of visual loss and is strongly associated with common haplotypes on chromosome 1 (CFH Y402H variant) and chromosome 10 (near HTRA1/ARMS2). In this study, the submacular tissue of older donors with genetic risk but without clinical features of AMD was analyzed using mass spectrometry-based quantitative proteomics. The results showed that the high-risk allele groups on chromosome 1 and chromosome 10 had common protein changes compared to the low-risk group, particularly increased levels of mast cell-specific proteases. Additional histological analyses revealed increased mast cells and denatured collagen in the submacular tissue of donors with genetic risk of AMD but without clinical features, as well as in donors with high-risk chromosome 1 alleles and early AMD. These findings suggest that increased mast cell infiltration, degranulation, and extracellular matrix remodeling are early events in AMD pathogenesis, and represent a mechanistic link between chromosome 1 and chromosome 10-mediated AMD.
Age-related macular degeneration (AMD) is a leading cause of visual loss. It has a strong genetic basis, and common haplotypes on chromosome (Chr) 1 (CFH Y402H variant) and on Chr10 (near HTRA1/ARMS2) contribute the most risk. Little is known about the early molecular and cellular processes in AMD, and we hypothesized that analyzing submacular tissue from older donors with genetic risk but without clinical features of AMD would provide biological insights. Therefore, we used mass spectrometry-based quantitative proteomics to compare the proteins in human submacular stromal tissue punches from donors who were homozygous for high-risk alleles at either Chr1 or Chr10 with those from donors who had protective haplotypes at these loci, all without clinical features of AMD. Additional comparisons were made with tissue from donors who were homozygous for high-risk Chr1 alleles and had early AMD. The Chr1 and Chr10 risk groups shared common changes compared with the low-risk group, particularly increased levels of mast cell-specific proteases, including tryptase, chymase, and carboxypeptidase A3. Histological analyses of submacular tissue from donors with genetic risk of AMD but without clinical features of AMD and from donors with Chr1 risk and AMD demonstrated increased mast cells, particularly the tryptase-positive/chymase-negative cells variety, along with increased levels of denatured collagen compared with tissue from low-genetic risk donors. We conclude that increased mast cell infiltration of the inner choroid, degranulation, and subsequent extracellular matrix remodeling are early events in AMD pathogenesis and represent a unifying mechanistic link between Chr1- and Chr10-mediated AMD.

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