Upregulation of P2RX7 in Cx3cr1-Deficient Mononuclear Phagocytes Leads to Increased Interleukin-1β Secretion and Photoreceptor Neurodegeneration
Photoreceptor degeneration in age-related macular degeneration (AMD) is associated with an infiltration and chronic accumulation of mononuclear phagocytes (MPs). We have previously shown that Cx3cr1-deficient mice develop age- and stress- related subretinal accumulation of MPs, which is associated w...
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| Veröffentlicht in: | The Journal of neuroscience 2015-05, Vol.35 (18), p.6987-6996 |
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| creator | Hu, Shulong J Calippe, Bertrand Lavalette, Sophie Roubeix, Christophe Montassar, Fadoua Housset, Michael Levy, Olivier Delarasse, Cecile Paques, Michel Sahel, José-Alain Sennlaub, Florian Guillonneau, Xavier |
| description | Photoreceptor degeneration in age-related macular degeneration (AMD) is associated with an infiltration and chronic accumulation of mononuclear phagocytes (MPs). We have previously shown that Cx3cr1-deficient mice develop age- and stress- related subretinal accumulation of MPs, which is associated with photoreceptor degeneration. Cx3cr1-deficient MPs have been shown to increase neuronal apoptosis through IL-1β in neuroinflammation of the brain. The reason for increased IL-1β secretion from Cx3cr1-deficient MPs, and whether IL-1β is responsible for increased photoreceptor apoptosis in Cx3cr1-deficient mice, has not been elucidated. Here we show that Cx3cr1-deficient MPs express increased surface P2X7 receptor (P2RX7), which stimulates IL-1β maturation and secretion. P2RX7 and IL-1β inhibition efficiently blunted Cx3cr1-MP-dependent photoreceptor apoptosis in a monocyte/retina coculture system and in light-induced subretinal inflammation of Cx3cr1-deficient mice in vivo. Our results provide an explanation for increased CX3CR1-dependent IL-1β secretion and suggest that IL-1β or P2RX7 inhibition can help inhibit the inflammation-associated photoreceptor cell loss in late AMD, including geographic atrophy, for which no efficient treatment currently exists. |
| doi_str_mv | 10.1523/JNEUROSCI.3955-14.2015 |
| format | Article |
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We have previously shown that Cx3cr1-deficient mice develop age- and stress- related subretinal accumulation of MPs, which is associated with photoreceptor degeneration. Cx3cr1-deficient MPs have been shown to increase neuronal apoptosis through IL-1β in neuroinflammation of the brain. The reason for increased IL-1β secretion from Cx3cr1-deficient MPs, and whether IL-1β is responsible for increased photoreceptor apoptosis in Cx3cr1-deficient mice, has not been elucidated. Here we show that Cx3cr1-deficient MPs express increased surface P2X7 receptor (P2RX7), which stimulates IL-1β maturation and secretion. P2RX7 and IL-1β inhibition efficiently blunted Cx3cr1-MP-dependent photoreceptor apoptosis in a monocyte/retina coculture system and in light-induced subretinal inflammation of Cx3cr1-deficient mice in vivo. Our results provide an explanation for increased CX3CR1-dependent IL-1β secretion and suggest that IL-1β or P2RX7 inhibition can help inhibit the inflammation-associated photoreceptor cell loss in late AMD, including geographic atrophy, for which no efficient treatment currently exists.</description><identifier>ISSN: 0270-6474</identifier><identifier>EISSN: 1529-2401</identifier><identifier>DOI: 10.1523/JNEUROSCI.3955-14.2015</identifier><identifier>PMID: 25948251</identifier><language>eng</language><publisher>United States: Society for Neuroscience</publisher><subject>Animals ; Coculture Techniques ; CX3C Chemokine Receptor 1 ; Female ; Interleukin-1beta - metabolism ; Macular Degeneration - metabolism ; Macular Degeneration - pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mononuclear Phagocyte System - metabolism ; Mononuclear Phagocyte System - pathology ; Phagocytes - metabolism ; Phagocytes - pathology ; Photoreceptor Cells - metabolism ; Photoreceptor Cells - pathology ; Receptors, Chemokine - deficiency ; Receptors, Purinergic P2X7 - biosynthesis ; Up-Regulation - physiology</subject><ispartof>The Journal of neuroscience, 2015-05, Vol.35 (18), p.6987-6996</ispartof><rights>Copyright © 2015 the authors 0270-6474/15/356987-10$15.00/0.</rights><rights>Copyright © 2015 the authors 0270-6474/15/356987-10$15.00/0 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c452t-fd7905b800350a7152eec504fdb813a677621ae82b0dc91ad573313b80bcfef23</citedby><cites>FETCH-LOGICAL-c452t-fd7905b800350a7152eec504fdb813a677621ae82b0dc91ad573313b80bcfef23</cites><orcidid>0000-0002-4831-1153 ; 0000-0001-7379-3935 ; 0000-0001-5029-2724</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605270/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605270/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25948251$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hu, Shulong J</creatorcontrib><creatorcontrib>Calippe, Bertrand</creatorcontrib><creatorcontrib>Lavalette, Sophie</creatorcontrib><creatorcontrib>Roubeix, Christophe</creatorcontrib><creatorcontrib>Montassar, Fadoua</creatorcontrib><creatorcontrib>Housset, Michael</creatorcontrib><creatorcontrib>Levy, Olivier</creatorcontrib><creatorcontrib>Delarasse, Cecile</creatorcontrib><creatorcontrib>Paques, Michel</creatorcontrib><creatorcontrib>Sahel, José-Alain</creatorcontrib><creatorcontrib>Sennlaub, Florian</creatorcontrib><creatorcontrib>Guillonneau, Xavier</creatorcontrib><title>Upregulation of P2RX7 in Cx3cr1-Deficient Mononuclear Phagocytes Leads to Increased Interleukin-1β Secretion and Photoreceptor Neurodegeneration</title><title>The Journal of neuroscience</title><addtitle>J Neurosci</addtitle><description>Photoreceptor degeneration in age-related macular degeneration (AMD) is associated with an infiltration and chronic accumulation of mononuclear phagocytes (MPs). We have previously shown that Cx3cr1-deficient mice develop age- and stress- related subretinal accumulation of MPs, which is associated with photoreceptor degeneration. Cx3cr1-deficient MPs have been shown to increase neuronal apoptosis through IL-1β in neuroinflammation of the brain. The reason for increased IL-1β secretion from Cx3cr1-deficient MPs, and whether IL-1β is responsible for increased photoreceptor apoptosis in Cx3cr1-deficient mice, has not been elucidated. Here we show that Cx3cr1-deficient MPs express increased surface P2X7 receptor (P2RX7), which stimulates IL-1β maturation and secretion. P2RX7 and IL-1β inhibition efficiently blunted Cx3cr1-MP-dependent photoreceptor apoptosis in a monocyte/retina coculture system and in light-induced subretinal inflammation of Cx3cr1-deficient mice in vivo. Our results provide an explanation for increased CX3CR1-dependent IL-1β secretion and suggest that IL-1β or P2RX7 inhibition can help inhibit the inflammation-associated photoreceptor cell loss in late AMD, including geographic atrophy, for which no efficient treatment currently exists.</description><subject>Animals</subject><subject>Coculture Techniques</subject><subject>CX3C Chemokine Receptor 1</subject><subject>Female</subject><subject>Interleukin-1beta - metabolism</subject><subject>Macular Degeneration - metabolism</subject><subject>Macular Degeneration - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mononuclear Phagocyte System - metabolism</subject><subject>Mononuclear Phagocyte System - pathology</subject><subject>Phagocytes - metabolism</subject><subject>Phagocytes - pathology</subject><subject>Photoreceptor Cells - metabolism</subject><subject>Photoreceptor Cells - pathology</subject><subject>Receptors, Chemokine - deficiency</subject><subject>Receptors, Purinergic P2X7 - biosynthesis</subject><subject>Up-Regulation - physiology</subject><issn>0270-6474</issn><issn>1529-2401</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUctuEzEUtRCIhsIvVF6ymeDneGaDhEKBoNBWLZHYWR77TmqY2MGeQfQz-BU-hG_CaUsEO1bX0nn4nnsQOqFkTiXjL96fna4vz68WyzlvpayomDNC5QM0K2hbMUHoQzQjTJGqFkocoSc5fyaEKELVY3TEZCsaJukM_VjvEmymwYw-Bhx7fMEuPynsA1585zbR6jX03noII_4QQwyTHcAkfHFtNtHejJDxCozLeIx4GWwCk8GV1whpgOmLDxX99RNfQUFuPzDBFW0cYwILuzLwGUwpOthAgHS7xFP0qDdDhmf38xit35x-XLyrVudvl4tXq8oKycaqd6olsmsI4ZIYVWIDWElE77qGclMrVTNqoGEdcbalxknFOeVF0NkeesaP0cs7393UbcHZEjGZQe-S35p0o6Px-l8k-Gu9id90XRNZDlsMnt8bpPh1gjzqrc8WhsEEiFPWVNWyVS1v_oNaN4S2JZco1PqOalPMOUF_2IgSva9eH6rX--o1FXpffRGe_J3nIPvTNf8NLUmu6A</recordid><startdate>20150506</startdate><enddate>20150506</enddate><creator>Hu, Shulong J</creator><creator>Calippe, Bertrand</creator><creator>Lavalette, Sophie</creator><creator>Roubeix, Christophe</creator><creator>Montassar, Fadoua</creator><creator>Housset, Michael</creator><creator>Levy, Olivier</creator><creator>Delarasse, Cecile</creator><creator>Paques, Michel</creator><creator>Sahel, José-Alain</creator><creator>Sennlaub, Florian</creator><creator>Guillonneau, Xavier</creator><general>Society for Neuroscience</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>7X8</scope><scope>7T5</scope><scope>7TK</scope><scope>H94</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4831-1153</orcidid><orcidid>https://orcid.org/0000-0001-7379-3935</orcidid><orcidid>https://orcid.org/0000-0001-5029-2724</orcidid></search><sort><creationdate>20150506</creationdate><title>Upregulation of P2RX7 in Cx3cr1-Deficient Mononuclear Phagocytes Leads to Increased Interleukin-1β Secretion and Photoreceptor Neurodegeneration</title><author>Hu, Shulong J ; Calippe, Bertrand ; Lavalette, Sophie ; Roubeix, Christophe ; Montassar, Fadoua ; Housset, Michael ; Levy, Olivier ; Delarasse, Cecile ; Paques, Michel ; Sahel, José-Alain ; Sennlaub, Florian ; Guillonneau, Xavier</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c452t-fd7905b800350a7152eec504fdb813a677621ae82b0dc91ad573313b80bcfef23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Coculture Techniques</topic><topic>CX3C Chemokine Receptor 1</topic><topic>Female</topic><topic>Interleukin-1beta - metabolism</topic><topic>Macular Degeneration - metabolism</topic><topic>Macular Degeneration - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mononuclear Phagocyte System - metabolism</topic><topic>Mononuclear Phagocyte System - pathology</topic><topic>Phagocytes - metabolism</topic><topic>Phagocytes - pathology</topic><topic>Photoreceptor Cells - metabolism</topic><topic>Photoreceptor Cells - pathology</topic><topic>Receptors, Chemokine - deficiency</topic><topic>Receptors, Purinergic P2X7 - biosynthesis</topic><topic>Up-Regulation - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hu, Shulong J</creatorcontrib><creatorcontrib>Calippe, Bertrand</creatorcontrib><creatorcontrib>Lavalette, Sophie</creatorcontrib><creatorcontrib>Roubeix, Christophe</creatorcontrib><creatorcontrib>Montassar, Fadoua</creatorcontrib><creatorcontrib>Housset, Michael</creatorcontrib><creatorcontrib>Levy, Olivier</creatorcontrib><creatorcontrib>Delarasse, Cecile</creatorcontrib><creatorcontrib>Paques, Michel</creatorcontrib><creatorcontrib>Sahel, José-Alain</creatorcontrib><creatorcontrib>Sennlaub, Florian</creatorcontrib><creatorcontrib>Guillonneau, Xavier</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hu, Shulong J</au><au>Calippe, Bertrand</au><au>Lavalette, Sophie</au><au>Roubeix, Christophe</au><au>Montassar, Fadoua</au><au>Housset, Michael</au><au>Levy, Olivier</au><au>Delarasse, Cecile</au><au>Paques, Michel</au><au>Sahel, José-Alain</au><au>Sennlaub, Florian</au><au>Guillonneau, Xavier</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Upregulation of P2RX7 in Cx3cr1-Deficient Mononuclear Phagocytes Leads to Increased Interleukin-1β Secretion and Photoreceptor Neurodegeneration</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2015-05-06</date><risdate>2015</risdate><volume>35</volume><issue>18</issue><spage>6987</spage><epage>6996</epage><pages>6987-6996</pages><issn>0270-6474</issn><eissn>1529-2401</eissn><abstract>Photoreceptor degeneration in age-related macular degeneration (AMD) is associated with an infiltration and chronic accumulation of mononuclear phagocytes (MPs). We have previously shown that Cx3cr1-deficient mice develop age- and stress- related subretinal accumulation of MPs, which is associated with photoreceptor degeneration. Cx3cr1-deficient MPs have been shown to increase neuronal apoptosis through IL-1β in neuroinflammation of the brain. The reason for increased IL-1β secretion from Cx3cr1-deficient MPs, and whether IL-1β is responsible for increased photoreceptor apoptosis in Cx3cr1-deficient mice, has not been elucidated. Here we show that Cx3cr1-deficient MPs express increased surface P2X7 receptor (P2RX7), which stimulates IL-1β maturation and secretion. P2RX7 and IL-1β inhibition efficiently blunted Cx3cr1-MP-dependent photoreceptor apoptosis in a monocyte/retina coculture system and in light-induced subretinal inflammation of Cx3cr1-deficient mice in vivo. Our results provide an explanation for increased CX3CR1-dependent IL-1β secretion and suggest that IL-1β or P2RX7 inhibition can help inhibit the inflammation-associated photoreceptor cell loss in late AMD, including geographic atrophy, for which no efficient treatment currently exists.</abstract><cop>United States</cop><pub>Society for Neuroscience</pub><pmid>25948251</pmid><doi>10.1523/JNEUROSCI.3955-14.2015</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-4831-1153</orcidid><orcidid>https://orcid.org/0000-0001-7379-3935</orcidid><orcidid>https://orcid.org/0000-0001-5029-2724</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animals Coculture Techniques CX3C Chemokine Receptor 1 Female Interleukin-1beta - metabolism Macular Degeneration - metabolism Macular Degeneration - pathology Male Mice Mice, Inbred C57BL Mice, Knockout Mononuclear Phagocyte System - metabolism Mononuclear Phagocyte System - pathology Phagocytes - metabolism Phagocytes - pathology Photoreceptor Cells - metabolism Photoreceptor Cells - pathology Receptors, Chemokine - deficiency Receptors, Purinergic P2X7 - biosynthesis Up-Regulation - physiology |
| title | Upregulation of P2RX7 in Cx3cr1-Deficient Mononuclear Phagocytes Leads to Increased Interleukin-1β Secretion and Photoreceptor Neurodegeneration |
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