The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination
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 p...
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| Veröffentlicht in: | Immunity (Cambridge, Mass.) Mass.), 2020-08, Vol.53 (2), p.429-441.e8 |
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| creator | Beguier, Fanny Housset, Michael Roubeix, Christophe Augustin, Sebastien Zagar, Yvrick Nous, Caroline Mathis, Thibaud Eandi, Chiara Benchaboune, Mustapha Drame-Maigné, Adèle Carpentier, Wassila Chardonnet, Solenne Touhami, Sara Blot, Guillaume Conart, Jean Baptiste Charles-Messance, Hugo Potey, Anaïs Girmens, Jean-François Paques, Michel Blond, Fréderic Leveillard, Thierry Koertvely, Elod Roger, Jerome E. Sahel, José-Alain Sapieha, Przemyslaw Delarasse, Cécile Guillonneau, Xavier Sennlaub, Florian |
| description | 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.
[Display omitted]
•10q26 AMD-risk haplotype carrying monocytes overexpress HTRA1 and OPN•HTRA1 locates to mononuclear phagocytes in eyes of patients with AMD•HTRA1 proteolysis of TSP-1 curbs CD47-dependent OPN repression•HTRA1 induced OPN promotes pathogenic subretinal MP accumulation
A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Beguier et al. provide a mechanistic understanding of this susceptibility by linking this risk haplotype to overexpression of the peptidase HTRA1 and thereby to the accumulation of macrophages in the subretinal space and pathogenic inflammation. |
| doi_str_mv | 10.1016/j.immuni.2020.07.021 |
| format | Article |
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[Display omitted]
•10q26 AMD-risk haplotype carrying monocytes overexpress HTRA1 and OPN•HTRA1 locates to mononuclear phagocytes in eyes of patients with AMD•HTRA1 proteolysis of TSP-1 curbs CD47-dependent OPN repression•HTRA1 induced OPN promotes pathogenic subretinal MP accumulation
A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Beguier et al. provide a mechanistic understanding of this susceptibility by linking this risk haplotype to overexpression of the peptidase HTRA1 and thereby to the accumulation of macrophages in the subretinal space and pathogenic inflammation.</description><identifier>ISSN: 1074-7613</identifier><identifier>EISSN: 1097-4180</identifier><identifier>DOI: 10.1016/j.immuni.2020.07.021</identifier><identifier>PMID: 32814029</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>10q26 ; Age ; Age related diseases ; age-related macular degeneration ; Amino acids ; Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism ; Binding sites ; Binding Sites - physiology ; Biomedical materials ; CD47 ; CD47 Antigen - metabolism ; Cell Line ; Chlorocebus aethiops ; choroidal neovascularization ; Chromosome 10 ; Chromosomes, Human, Pair 10 - genetics ; COS Cells ; Eye - pathology ; Eye diseases ; Genetic Predisposition to Disease - genetics ; Haplotypes ; Health risk assessment ; high-temperature requirement a serine peptidase 1 ; High-Temperature Requirement A Serine Peptidase 1 - genetics ; High-Temperature Requirement A Serine Peptidase 1 - metabolism ; Humans ; Inflammation ; Leukocytes (mononuclear) ; Life Sciences ; Lymphocytes ; Macrophages ; Macrophages - immunology ; Macrophages - pathology ; Macular degeneration ; Macular Degeneration - genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Monocytes ; Monocytes - metabolism ; mononuclear phagocytes ; neuro-inflammation ; Osteopontin ; Osteopontin - metabolism ; Peptides ; Phagocytes ; Proteins ; Retina ; Risk ; Serine ; Serine peptidase ; Signal Transduction - genetics ; Thrombospondin ; thrombospondin 1</subject><ispartof>Immunity (Cambridge, Mass.), 2020-08, Vol.53 (2), p.429-441.e8</ispartof><rights>2020 Elsevier Inc.</rights><rights>Copyright © 2020 Elsevier Inc. All rights reserved.</rights><rights>2020. Elsevier Inc.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c539t-cf492e25d0b1ad30271d882fe36452abf3dc276766aeda8ab06723ae8e6d55c03</citedby><cites>FETCH-LOGICAL-c539t-cf492e25d0b1ad30271d882fe36452abf3dc276766aeda8ab06723ae8e6d55c03</cites><orcidid>0000-0002-1418-1872 ; 0000-0001-5032-6306 ; 0000-0002-3892-5696 ; 0000-0001-8346-3067 ; 0000-0002-9102-9196 ; 0000-0002-4831-1153 ; 0000-0001-9968-0074</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.immuni.2020.07.021$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32814029$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://inserm.hal.science/inserm-02933674$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Beguier, Fanny</creatorcontrib><creatorcontrib>Housset, Michael</creatorcontrib><creatorcontrib>Roubeix, Christophe</creatorcontrib><creatorcontrib>Augustin, Sebastien</creatorcontrib><creatorcontrib>Zagar, Yvrick</creatorcontrib><creatorcontrib>Nous, Caroline</creatorcontrib><creatorcontrib>Mathis, Thibaud</creatorcontrib><creatorcontrib>Eandi, Chiara</creatorcontrib><creatorcontrib>Benchaboune, Mustapha</creatorcontrib><creatorcontrib>Drame-Maigné, Adèle</creatorcontrib><creatorcontrib>Carpentier, Wassila</creatorcontrib><creatorcontrib>Chardonnet, Solenne</creatorcontrib><creatorcontrib>Touhami, Sara</creatorcontrib><creatorcontrib>Blot, Guillaume</creatorcontrib><creatorcontrib>Conart, Jean Baptiste</creatorcontrib><creatorcontrib>Charles-Messance, Hugo</creatorcontrib><creatorcontrib>Potey, Anaïs</creatorcontrib><creatorcontrib>Girmens, Jean-François</creatorcontrib><creatorcontrib>Paques, Michel</creatorcontrib><creatorcontrib>Blond, Fréderic</creatorcontrib><creatorcontrib>Leveillard, Thierry</creatorcontrib><creatorcontrib>Koertvely, Elod</creatorcontrib><creatorcontrib>Roger, Jerome E.</creatorcontrib><creatorcontrib>Sahel, José-Alain</creatorcontrib><creatorcontrib>Sapieha, Przemyslaw</creatorcontrib><creatorcontrib>Delarasse, Cécile</creatorcontrib><creatorcontrib>Guillonneau, Xavier</creatorcontrib><creatorcontrib>Sennlaub, Florian</creatorcontrib><title>The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination</title><title>Immunity (Cambridge, Mass.)</title><addtitle>Immunity</addtitle><description>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.
[Display omitted]
•10q26 AMD-risk haplotype carrying monocytes overexpress HTRA1 and OPN•HTRA1 locates to mononuclear phagocytes in eyes of patients with AMD•HTRA1 proteolysis of TSP-1 curbs CD47-dependent OPN repression•HTRA1 induced OPN promotes pathogenic subretinal MP accumulation
A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Beguier et al. provide a mechanistic understanding of this susceptibility by linking this risk haplotype to overexpression of the peptidase HTRA1 and thereby to the accumulation of macrophages in the subretinal space and pathogenic inflammation.</description><subject>10q26</subject><subject>Age</subject><subject>Age related diseases</subject><subject>age-related macular degeneration</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism</subject><subject>Binding sites</subject><subject>Binding Sites - physiology</subject><subject>Biomedical materials</subject><subject>CD47</subject><subject>CD47 Antigen - metabolism</subject><subject>Cell Line</subject><subject>Chlorocebus aethiops</subject><subject>choroidal neovascularization</subject><subject>Chromosome 10</subject><subject>Chromosomes, Human, Pair 10 - genetics</subject><subject>COS Cells</subject><subject>Eye - pathology</subject><subject>Eye diseases</subject><subject>Genetic Predisposition to Disease - genetics</subject><subject>Haplotypes</subject><subject>Health risk assessment</subject><subject>high-temperature requirement a serine peptidase 1</subject><subject>High-Temperature Requirement A Serine Peptidase 1 - genetics</subject><subject>High-Temperature Requirement A Serine Peptidase 1 - metabolism</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Leukocytes (mononuclear)</subject><subject>Life Sciences</subject><subject>Lymphocytes</subject><subject>Macrophages</subject><subject>Macrophages - immunology</subject><subject>Macrophages - pathology</subject><subject>Macular degeneration</subject><subject>Macular Degeneration - genetics</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Monocytes</subject><subject>Monocytes - metabolism</subject><subject>mononuclear phagocytes</subject><subject>neuro-inflammation</subject><subject>Osteopontin</subject><subject>Osteopontin - metabolism</subject><subject>Peptides</subject><subject>Phagocytes</subject><subject>Proteins</subject><subject>Retina</subject><subject>Risk</subject><subject>Serine</subject><subject>Serine peptidase</subject><subject>Signal Transduction - genetics</subject><subject>Thrombospondin</subject><subject>thrombospondin 1</subject><issn>1074-7613</issn><issn>1097-4180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90U1v1DAQBuAIgegH_AOELHHhQBZ_JHZyQVqVwq60FVIpZ8txJlsvjp3ayUp75J_XUUoPHDjZkp8Zj-bNsncErwgm_PNhZfp-cmZFMcUrLFaYkhfZOcG1yAtS4ZfzXRS54ISdZRcxHjAmRVnj19kZoxUpMK3Psz9394AIfqAc3Zr4G23UYP14GgD5Dq33kN-CVSO06EbpyaqAvsIeHAQ1Gu8S2Ad1TO8R_ZyaAKNxyqKt66zq-4U0J7TtB2WCcXt0453XpxHQtTV9srN4k73qlI3w9um8zH59u7672uS7H9-3V-tdrktWj7nuipoCLVvcENUyTAVpq4p2wHhRUtV0rNVUcMG5glZVqsFcUKagAt6WpcbsMvu09L1XVg7B9CqcpFdGbtY7aVyE0Mu0Esa4KI4k8Y8LH4J_mCCOsjdRg7XKgZ-ipAUrRVkKxhL98A89-CmkTSwqZSFomVSxKB18jAG65yEIlnOi8iCXROWcqMQijTPP8f6p-dT00D4X_Y0wgS8LgLS8o4EgozbgNLQmgB5l683_f3gE4Qizjw</recordid><startdate>20200818</startdate><enddate>20200818</enddate><creator>Beguier, Fanny</creator><creator>Housset, Michael</creator><creator>Roubeix, Christophe</creator><creator>Augustin, Sebastien</creator><creator>Zagar, Yvrick</creator><creator>Nous, Caroline</creator><creator>Mathis, Thibaud</creator><creator>Eandi, Chiara</creator><creator>Benchaboune, Mustapha</creator><creator>Drame-Maigné, Adèle</creator><creator>Carpentier, Wassila</creator><creator>Chardonnet, Solenne</creator><creator>Touhami, Sara</creator><creator>Blot, Guillaume</creator><creator>Conart, Jean Baptiste</creator><creator>Charles-Messance, Hugo</creator><creator>Potey, Anaïs</creator><creator>Girmens, Jean-François</creator><creator>Paques, Michel</creator><creator>Blond, Fréderic</creator><creator>Leveillard, Thierry</creator><creator>Koertvely, Elod</creator><creator>Roger, Jerome E.</creator><creator>Sahel, José-Alain</creator><creator>Sapieha, Przemyslaw</creator><creator>Delarasse, Cécile</creator><creator>Guillonneau, Xavier</creator><creator>Sennlaub, Florian</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><general>Elsevier</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><orcidid>https://orcid.org/0000-0002-1418-1872</orcidid><orcidid>https://orcid.org/0000-0001-5032-6306</orcidid><orcidid>https://orcid.org/0000-0002-3892-5696</orcidid><orcidid>https://orcid.org/0000-0001-8346-3067</orcidid><orcidid>https://orcid.org/0000-0002-9102-9196</orcidid><orcidid>https://orcid.org/0000-0002-4831-1153</orcidid><orcidid>https://orcid.org/0000-0001-9968-0074</orcidid></search><sort><creationdate>20200818</creationdate><title>The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination</title><author>Beguier, Fanny ; Housset, Michael ; Roubeix, Christophe ; Augustin, Sebastien ; Zagar, Yvrick ; Nous, Caroline ; Mathis, Thibaud ; Eandi, Chiara ; Benchaboune, Mustapha ; Drame-Maigné, Adèle ; Carpentier, Wassila ; Chardonnet, Solenne ; Touhami, Sara ; Blot, Guillaume ; Conart, Jean Baptiste ; Charles-Messance, Hugo ; Potey, Anaïs ; Girmens, Jean-François ; Paques, Michel ; Blond, Fréderic ; Leveillard, Thierry ; Koertvely, Elod ; Roger, Jerome E. ; Sahel, José-Alain ; Sapieha, Przemyslaw ; Delarasse, Cécile ; Guillonneau, Xavier ; Sennlaub, Florian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c539t-cf492e25d0b1ad30271d882fe36452abf3dc276766aeda8ab06723ae8e6d55c03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>10q26</topic><topic>Age</topic><topic>Age related diseases</topic><topic>age-related macular degeneration</topic><topic>Amino acids</topic><topic>Animals</topic><topic>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism</topic><topic>Binding sites</topic><topic>Binding Sites - physiology</topic><topic>Biomedical materials</topic><topic>CD47</topic><topic>CD47 Antigen - metabolism</topic><topic>Cell Line</topic><topic>Chlorocebus aethiops</topic><topic>choroidal neovascularization</topic><topic>Chromosome 10</topic><topic>Chromosomes, Human, Pair 10 - genetics</topic><topic>COS Cells</topic><topic>Eye - pathology</topic><topic>Eye diseases</topic><topic>Genetic Predisposition to Disease - genetics</topic><topic>Haplotypes</topic><topic>Health risk assessment</topic><topic>high-temperature requirement a serine peptidase 1</topic><topic>High-Temperature Requirement A Serine Peptidase 1 - genetics</topic><topic>High-Temperature Requirement A Serine Peptidase 1 - metabolism</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Leukocytes (mononuclear)</topic><topic>Life Sciences</topic><topic>Lymphocytes</topic><topic>Macrophages</topic><topic>Macrophages - immunology</topic><topic>Macrophages - pathology</topic><topic>Macular degeneration</topic><topic>Macular Degeneration - genetics</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Monocytes</topic><topic>Monocytes - metabolism</topic><topic>mononuclear phagocytes</topic><topic>neuro-inflammation</topic><topic>Osteopontin</topic><topic>Osteopontin - metabolism</topic><topic>Peptides</topic><topic>Phagocytes</topic><topic>Proteins</topic><topic>Retina</topic><topic>Risk</topic><topic>Serine</topic><topic>Serine peptidase</topic><topic>Signal Transduction - genetics</topic><topic>Thrombospondin</topic><topic>thrombospondin 1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Beguier, Fanny</creatorcontrib><creatorcontrib>Housset, Michael</creatorcontrib><creatorcontrib>Roubeix, Christophe</creatorcontrib><creatorcontrib>Augustin, Sebastien</creatorcontrib><creatorcontrib>Zagar, Yvrick</creatorcontrib><creatorcontrib>Nous, Caroline</creatorcontrib><creatorcontrib>Mathis, Thibaud</creatorcontrib><creatorcontrib>Eandi, Chiara</creatorcontrib><creatorcontrib>Benchaboune, Mustapha</creatorcontrib><creatorcontrib>Drame-Maigné, Adèle</creatorcontrib><creatorcontrib>Carpentier, Wassila</creatorcontrib><creatorcontrib>Chardonnet, Solenne</creatorcontrib><creatorcontrib>Touhami, Sara</creatorcontrib><creatorcontrib>Blot, Guillaume</creatorcontrib><creatorcontrib>Conart, Jean Baptiste</creatorcontrib><creatorcontrib>Charles-Messance, Hugo</creatorcontrib><creatorcontrib>Potey, Anaïs</creatorcontrib><creatorcontrib>Girmens, Jean-François</creatorcontrib><creatorcontrib>Paques, Michel</creatorcontrib><creatorcontrib>Blond, Fréderic</creatorcontrib><creatorcontrib>Leveillard, Thierry</creatorcontrib><creatorcontrib>Koertvely, Elod</creatorcontrib><creatorcontrib>Roger, Jerome E.</creatorcontrib><creatorcontrib>Sahel, José-Alain</creatorcontrib><creatorcontrib>Sapieha, Przemyslaw</creatorcontrib><creatorcontrib>Delarasse, Cécile</creatorcontrib><creatorcontrib>Guillonneau, Xavier</creatorcontrib><creatorcontrib>Sennlaub, Florian</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><jtitle>Immunity (Cambridge, Mass.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Beguier, Fanny</au><au>Housset, Michael</au><au>Roubeix, Christophe</au><au>Augustin, Sebastien</au><au>Zagar, Yvrick</au><au>Nous, Caroline</au><au>Mathis, Thibaud</au><au>Eandi, Chiara</au><au>Benchaboune, Mustapha</au><au>Drame-Maigné, Adèle</au><au>Carpentier, Wassila</au><au>Chardonnet, Solenne</au><au>Touhami, Sara</au><au>Blot, Guillaume</au><au>Conart, Jean Baptiste</au><au>Charles-Messance, Hugo</au><au>Potey, Anaïs</au><au>Girmens, Jean-François</au><au>Paques, Michel</au><au>Blond, Fréderic</au><au>Leveillard, Thierry</au><au>Koertvely, Elod</au><au>Roger, Jerome E.</au><au>Sahel, José-Alain</au><au>Sapieha, Przemyslaw</au><au>Delarasse, Cécile</au><au>Guillonneau, Xavier</au><au>Sennlaub, Florian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination</atitle><jtitle>Immunity (Cambridge, Mass.)</jtitle><addtitle>Immunity</addtitle><date>2020-08-18</date><risdate>2020</risdate><volume>53</volume><issue>2</issue><spage>429</spage><epage>441.e8</epage><pages>429-441.e8</pages><issn>1074-7613</issn><eissn>1097-4180</eissn><abstract>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.
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•10q26 AMD-risk haplotype carrying monocytes overexpress HTRA1 and OPN•HTRA1 locates to mononuclear phagocytes in eyes of patients with AMD•HTRA1 proteolysis of TSP-1 curbs CD47-dependent OPN repression•HTRA1 induced OPN promotes pathogenic subretinal MP accumulation
A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Beguier et al. provide a mechanistic understanding of this susceptibility by linking this risk haplotype to overexpression of the peptidase HTRA1 and thereby to the accumulation of macrophages in the subretinal space and pathogenic inflammation.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32814029</pmid><doi>10.1016/j.immuni.2020.07.021</doi><orcidid>https://orcid.org/0000-0002-1418-1872</orcidid><orcidid>https://orcid.org/0000-0001-5032-6306</orcidid><orcidid>https://orcid.org/0000-0002-3892-5696</orcidid><orcidid>https://orcid.org/0000-0001-8346-3067</orcidid><orcidid>https://orcid.org/0000-0002-9102-9196</orcidid><orcidid>https://orcid.org/0000-0002-4831-1153</orcidid><orcidid>https://orcid.org/0000-0001-9968-0074</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1074-7613 |
| ispartof | Immunity (Cambridge, Mass.), 2020-08, Vol.53 (2), p.429-441.e8 |
| issn | 1074-7613 1097-4180 |
| language | eng |
| recordid | cdi_hal_primary_oai_HAL_inserm_02933674v1 |
| source | MEDLINE; Cell Press Free Archives; Access via ScienceDirect (Elsevier); EZB-FREE-00999 freely available EZB journals |
| subjects | 10q26 Age Age related diseases age-related macular degeneration Amino acids Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism Binding sites Binding Sites - physiology Biomedical materials CD47 CD47 Antigen - metabolism Cell Line Chlorocebus aethiops choroidal neovascularization Chromosome 10 Chromosomes, Human, Pair 10 - genetics COS Cells Eye - pathology Eye diseases Genetic Predisposition to Disease - genetics Haplotypes Health risk assessment high-temperature requirement a serine peptidase 1 High-Temperature Requirement A Serine Peptidase 1 - genetics High-Temperature Requirement A Serine Peptidase 1 - metabolism Humans Inflammation Leukocytes (mononuclear) Life Sciences Lymphocytes Macrophages Macrophages - immunology Macrophages - pathology Macular degeneration Macular Degeneration - genetics Mice Mice, Inbred C57BL Mice, Knockout Monocytes Monocytes - metabolism mononuclear phagocytes neuro-inflammation Osteopontin Osteopontin - metabolism Peptides Phagocytes Proteins Retina Risk Serine Serine peptidase Signal Transduction - genetics Thrombospondin thrombospondin 1 |
| title | The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-23T11%3A52%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_hal_p&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%2010q26%20Risk%20Haplotype%20of%20Age-Related%20Macular%20Degeneration%20Aggravates%20Subretinal%20Inflammation%20by%20Impairing%20Monocyte%20Elimination&rft.jtitle=Immunity%20(Cambridge,%20Mass.)&rft.au=Beguier,%20Fanny&rft.date=2020-08-18&rft.volume=53&rft.issue=2&rft.spage=429&rft.epage=441.e8&rft.pages=429-441.e8&rft.issn=1074-7613&rft.eissn=1097-4180&rft_id=info:doi/10.1016/j.immuni.2020.07.021&rft_dat=%3Cproquest_hal_p%3E2435755733%3C/proquest_hal_p%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2435180725&rft_id=info:pmid/32814029&rft_els_id=S1074761320303289&rfr_iscdi=true |