Proinflammatory signaling in islet β cells propagates invasion of pathogenic immune cells in autoimmune diabetes
Type 1 diabetes is a disorder of immune tolerance that leads to death of insulin-producing islet β cells. We hypothesize that inflammatory signaling within β cells promotes progression of autoimmunity within the islet microenvironment. To test this hypothesis, we deleted the proinflammatory gene enc...
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| Veröffentlicht in: | Cell reports (Cambridge) 2022-06, Vol.39 (13), p.111011-111011, Article 111011 |
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| creator | Piñeros, Annie R Kulkarni, Abhishek Gao, Hongyu Orr, Kara S Glenn, Lindsey Huang, Fei Liu, Yunlong Gannon, Maureen Syed, Farooq Wu, Wenting Anderson, Cara M Evans-Molina, Carmella McDuffie, Marcia Nadler, Jerry L Morris, Margaret A Mirmira, Raghavendra G Tersey, Sarah A |
| description | Type 1 diabetes is a disorder of immune tolerance that leads to death of insulin-producing islet β cells. We hypothesize that inflammatory signaling within β cells promotes progression of autoimmunity within the islet microenvironment. To test this hypothesis, we deleted the proinflammatory gene encoding 12/15-lipoxygenase (Alox15) in β cells of non-obese diabetic mice at a pre-diabetic time point when islet inflammation is a feature. Deletion of Alox15 leads to preservation of β cell mass, reduces populations of infiltrating T cells, and protects against spontaneous autoimmune diabetes in both sexes. Mice lacking Alox15 in β cells exhibit an increase in a population of β cells expressing the gene encoding the protein programmed death ligand 1 (PD-L1), which engages receptors on immune cells to suppress autoimmunity. Delivery of a monoclonal antibody against PD-L1 recovers the diabetes phenotype in knockout animals. Our results support the contention that inflammatory signaling in β cells promotes autoimmunity during type 1 diabetes progression. |
| doi_str_mv | 10.1016/j.celrep.2022.111011 |
| format | Article |
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We hypothesize that inflammatory signaling within β cells promotes progression of autoimmunity within the islet microenvironment. To test this hypothesis, we deleted the proinflammatory gene encoding 12/15-lipoxygenase (Alox15) in β cells of non-obese diabetic mice at a pre-diabetic time point when islet inflammation is a feature. Deletion of Alox15 leads to preservation of β cell mass, reduces populations of infiltrating T cells, and protects against spontaneous autoimmune diabetes in both sexes. Mice lacking Alox15 in β cells exhibit an increase in a population of β cells expressing the gene encoding the protein programmed death ligand 1 (PD-L1), which engages receptors on immune cells to suppress autoimmunity. Delivery of a monoclonal antibody against PD-L1 recovers the diabetes phenotype in knockout animals. Our results support the contention that inflammatory signaling in β cells promotes autoimmunity during type 1 diabetes progression.</description><identifier>ISSN: 2211-1247</identifier><identifier>EISSN: 2211-1247</identifier><identifier>DOI: 10.1016/j.celrep.2022.111011</identifier><identifier>PMID: 35767947</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; B7-H1 Antigen - metabolism ; Diabetes Mellitus, Experimental - metabolism ; Diabetes Mellitus, Type 1 ; Female ; Islets of Langerhans - metabolism ; Male ; Mice ; Mice, Inbred NOD</subject><ispartof>Cell reports (Cambridge), 2022-06, Vol.39 (13), p.111011-111011, Article 111011</ispartof><rights>Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-3bfa79341fda1df0f79469b0ffef6cb129fea2b75ebe5942ff6356046cc4f36a3</citedby><cites>FETCH-LOGICAL-c408t-3bfa79341fda1df0f79469b0ffef6cb129fea2b75ebe5942ff6356046cc4f36a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,782,786,866,887,27931,27932</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35767947$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Piñeros, Annie R</creatorcontrib><creatorcontrib>Kulkarni, Abhishek</creatorcontrib><creatorcontrib>Gao, Hongyu</creatorcontrib><creatorcontrib>Orr, Kara S</creatorcontrib><creatorcontrib>Glenn, Lindsey</creatorcontrib><creatorcontrib>Huang, Fei</creatorcontrib><creatorcontrib>Liu, Yunlong</creatorcontrib><creatorcontrib>Gannon, Maureen</creatorcontrib><creatorcontrib>Syed, Farooq</creatorcontrib><creatorcontrib>Wu, Wenting</creatorcontrib><creatorcontrib>Anderson, Cara M</creatorcontrib><creatorcontrib>Evans-Molina, Carmella</creatorcontrib><creatorcontrib>McDuffie, Marcia</creatorcontrib><creatorcontrib>Nadler, Jerry L</creatorcontrib><creatorcontrib>Morris, Margaret A</creatorcontrib><creatorcontrib>Mirmira, Raghavendra G</creatorcontrib><creatorcontrib>Tersey, Sarah A</creatorcontrib><title>Proinflammatory signaling in islet β cells propagates invasion of pathogenic immune cells in autoimmune diabetes</title><title>Cell reports (Cambridge)</title><addtitle>Cell Rep</addtitle><description>Type 1 diabetes is a disorder of immune tolerance that leads to death of insulin-producing islet β cells. We hypothesize that inflammatory signaling within β cells promotes progression of autoimmunity within the islet microenvironment. To test this hypothesis, we deleted the proinflammatory gene encoding 12/15-lipoxygenase (Alox15) in β cells of non-obese diabetic mice at a pre-diabetic time point when islet inflammation is a feature. Deletion of Alox15 leads to preservation of β cell mass, reduces populations of infiltrating T cells, and protects against spontaneous autoimmune diabetes in both sexes. Mice lacking Alox15 in β cells exhibit an increase in a population of β cells expressing the gene encoding the protein programmed death ligand 1 (PD-L1), which engages receptors on immune cells to suppress autoimmunity. Delivery of a monoclonal antibody against PD-L1 recovers the diabetes phenotype in knockout animals. Our results support the contention that inflammatory signaling in β cells promotes autoimmunity during type 1 diabetes progression.</description><subject>Animals</subject><subject>B7-H1 Antigen - metabolism</subject><subject>Diabetes Mellitus, Experimental - metabolism</subject><subject>Diabetes Mellitus, Type 1</subject><subject>Female</subject><subject>Islets of Langerhans - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><issn>2211-1247</issn><issn>2211-1247</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkcFO4zAQhi20iCLgDdDKx720azuO3VxWWlULrITEHpazNUnHqavETu0EidfiQXgmXLUg8MXWzP__M9ZHyDVnC864-rldNNhFHBaCCbHgPBf5CTkXgvM5F1J_-_SekauUtiwflVWVPCOzotRKV1Kfk92_GJy3HfQ9jCE-0-RaD53zLXWeutThSF9faJ7WJTrEMEALI6bcfILkgqfB0gHGTWjRu4a6vp88HuU5AKYxHGtrBzVm6yU5tdAlvDreF-Tx5s__1d38_uH27-r3_byRbDnOi9qCrgrJ7Rr42jKb91VVzaxFq5qai8oiiFqXWGNZSWGtKkrFpGoaaQsFxQX5dcgdprrHdYN-jNCZIboe4rMJ4MzXjncb04YnU4lKa85zwI9jQAy7CdNoepf2PwOPYUpGqKXQS83LZZbKg7SJIaWI9mMMZ2YPzGzNAZjZAzMHYNn2_fOKH6Z3PMUbd8OYtg</recordid><startdate>20220628</startdate><enddate>20220628</enddate><creator>Piñeros, Annie R</creator><creator>Kulkarni, Abhishek</creator><creator>Gao, Hongyu</creator><creator>Orr, Kara S</creator><creator>Glenn, Lindsey</creator><creator>Huang, Fei</creator><creator>Liu, Yunlong</creator><creator>Gannon, Maureen</creator><creator>Syed, Farooq</creator><creator>Wu, Wenting</creator><creator>Anderson, Cara M</creator><creator>Evans-Molina, Carmella</creator><creator>McDuffie, Marcia</creator><creator>Nadler, Jerry L</creator><creator>Morris, Margaret A</creator><creator>Mirmira, Raghavendra G</creator><creator>Tersey, Sarah A</creator><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>5PM</scope></search><sort><creationdate>20220628</creationdate><title>Proinflammatory signaling in islet β cells propagates invasion of pathogenic immune cells in autoimmune diabetes</title><author>Piñeros, Annie R ; 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We hypothesize that inflammatory signaling within β cells promotes progression of autoimmunity within the islet microenvironment. To test this hypothesis, we deleted the proinflammatory gene encoding 12/15-lipoxygenase (Alox15) in β cells of non-obese diabetic mice at a pre-diabetic time point when islet inflammation is a feature. Deletion of Alox15 leads to preservation of β cell mass, reduces populations of infiltrating T cells, and protects against spontaneous autoimmune diabetes in both sexes. Mice lacking Alox15 in β cells exhibit an increase in a population of β cells expressing the gene encoding the protein programmed death ligand 1 (PD-L1), which engages receptors on immune cells to suppress autoimmunity. Delivery of a monoclonal antibody against PD-L1 recovers the diabetes phenotype in knockout animals. 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| source | MEDLINE; DOAJ Directory of Open Access Journals; Cell Press Free Archives; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals B7-H1 Antigen - metabolism Diabetes Mellitus, Experimental - metabolism Diabetes Mellitus, Type 1 Female Islets of Langerhans - metabolism Male Mice Mice, Inbred NOD |
| title | Proinflammatory signaling in islet β cells propagates invasion of pathogenic immune cells in autoimmune diabetes |
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