GPR41 deficiency aggravates type 1 diabetes in streptozotocin-treated mice by promoting dendritic cell maturation
Disturbances in intestinal immune homeostasis predispose susceptible individuals to type 1 diabetes (T1D). G-protein-coupled receptor 41 (GPR41) is a receptor for short-chain fatty acids (SCFAs) mainly produced by gut microbiota, which plays key roles in maintaining intestinal homeostasis. In this s...
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| Veröffentlicht in: | Acta pharmacologica Sinica 2024-07, Vol.45 (7), p.1466-1476 |
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| creator | Li, Jia-hong Zhang, Ming Zhang, Zhao-di Pan, Xiao-hua Pan, Li-long Sun, Jia |
| description | Disturbances in intestinal immune homeostasis predispose susceptible individuals to type 1 diabetes (T1D). G-protein-coupled receptor 41 (GPR41) is a receptor for short-chain fatty acids (SCFAs) mainly produced by gut microbiota, which plays key roles in maintaining intestinal homeostasis. In this study, we investigated the role of GPR41 in the progression of T1D. In non-obese diabetic (NOD) mice, we found that aberrant reduction of GPR41 expression in the pancreas and colons was associated with the development of T1D. GPR41-deficient (
Gpr41
−/−
) mice displayed significantly exacerbated streptozotocin (STZ)-induced T1D compared to wild-type mice. Furthermore,
Gpr41
−/−
mice showed enhanced gut immune dysregulation and increased migration of gut-primed IFN-γ
+
T cells to the pancreas. In bone marrow-derived dendritic cells from
Gpr41
−/−
mice, the expression of suppressor of cytokine signaling 3 (SOCS) was significantly inhibited, while the phosphorylation of STAT3 was significantly increased, thus promoting dendritic cell (DC) maturation. Furthermore, adoptive transfer of bone marrow-derived dendritic cells (BMDC) from
Gpr41
−/−
mice accelerated T1D in irradiated NOD mice. We conclude that GPR41 is essential for maintaining intestinal and pancreatic immune homeostasis and acts as a negative regulator of DC maturation in T1D. GPR41 may be a potential therapeutic target for T1D. |
| doi_str_mv | 10.1038/s41401-024-01242-7 |
| format | Article |
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Gpr41
−/−
) mice displayed significantly exacerbated streptozotocin (STZ)-induced T1D compared to wild-type mice. Furthermore,
Gpr41
−/−
mice showed enhanced gut immune dysregulation and increased migration of gut-primed IFN-γ
+
T cells to the pancreas. In bone marrow-derived dendritic cells from
Gpr41
−/−
mice, the expression of suppressor of cytokine signaling 3 (SOCS) was significantly inhibited, while the phosphorylation of STAT3 was significantly increased, thus promoting dendritic cell (DC) maturation. Furthermore, adoptive transfer of bone marrow-derived dendritic cells (BMDC) from
Gpr41
−/−
mice accelerated T1D in irradiated NOD mice. We conclude that GPR41 is essential for maintaining intestinal and pancreatic immune homeostasis and acts as a negative regulator of DC maturation in T1D. GPR41 may be a potential therapeutic target for T1D.</description><identifier>ISSN: 1671-4083</identifier><identifier>ISSN: 1745-7254</identifier><identifier>EISSN: 1745-7254</identifier><identifier>DOI: 10.1038/s41401-024-01242-7</identifier><identifier>PMID: 38514862</identifier><language>eng</language><publisher>Singapore: Springer Nature Singapore</publisher><subject>Animals ; Biomedical and Life Sciences ; Biomedicine ; Dendritic Cells - immunology ; Dendritic Cells - metabolism ; Diabetes Mellitus, Experimental - immunology ; Diabetes Mellitus, Experimental - metabolism ; Diabetes Mellitus, Type 1 - immunology ; Diabetes Mellitus, Type 1 - metabolism ; Female ; Gastrointestinal Microbiome ; Immunology ; Interferon-gamma - metabolism ; Internal Medicine ; Male ; Medical Microbiology ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, Knockout ; Pancreas - immunology ; Pancreas - metabolism ; Pancreas - pathology ; Pharmacology/Toxicology ; Receptors, G-Protein-Coupled - deficiency ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - metabolism ; STAT3 Transcription Factor - metabolism ; Streptozocin ; Suppressor of Cytokine Signaling 3 Protein - genetics ; Suppressor of Cytokine Signaling 3 Protein - metabolism ; Vaccine</subject><ispartof>Acta pharmacologica Sinica, 2024-07, Vol.45 (7), p.1466-1476</ispartof><rights>The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c298t-fc0468c58683fb5fd92fb58be3a73fe4bfaf88207f7ed5fd33fc3ae2919933513</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38514862$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Jia-hong</creatorcontrib><creatorcontrib>Zhang, Ming</creatorcontrib><creatorcontrib>Zhang, Zhao-di</creatorcontrib><creatorcontrib>Pan, Xiao-hua</creatorcontrib><creatorcontrib>Pan, Li-long</creatorcontrib><creatorcontrib>Sun, Jia</creatorcontrib><title>GPR41 deficiency aggravates type 1 diabetes in streptozotocin-treated mice by promoting dendritic cell maturation</title><title>Acta pharmacologica Sinica</title><addtitle>Acta Pharmacol Sin</addtitle><addtitle>Acta Pharmacol Sin</addtitle><description>Disturbances in intestinal immune homeostasis predispose susceptible individuals to type 1 diabetes (T1D). G-protein-coupled receptor 41 (GPR41) is a receptor for short-chain fatty acids (SCFAs) mainly produced by gut microbiota, which plays key roles in maintaining intestinal homeostasis. In this study, we investigated the role of GPR41 in the progression of T1D. In non-obese diabetic (NOD) mice, we found that aberrant reduction of GPR41 expression in the pancreas and colons was associated with the development of T1D. GPR41-deficient (
Gpr41
−/−
) mice displayed significantly exacerbated streptozotocin (STZ)-induced T1D compared to wild-type mice. Furthermore,
Gpr41
−/−
mice showed enhanced gut immune dysregulation and increased migration of gut-primed IFN-γ
+
T cells to the pancreas. In bone marrow-derived dendritic cells from
Gpr41
−/−
mice, the expression of suppressor of cytokine signaling 3 (SOCS) was significantly inhibited, while the phosphorylation of STAT3 was significantly increased, thus promoting dendritic cell (DC) maturation. Furthermore, adoptive transfer of bone marrow-derived dendritic cells (BMDC) from
Gpr41
−/−
mice accelerated T1D in irradiated NOD mice. We conclude that GPR41 is essential for maintaining intestinal and pancreatic immune homeostasis and acts as a negative regulator of DC maturation in T1D. GPR41 may be a potential therapeutic target for T1D.</description><subject>Animals</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Dendritic Cells - immunology</subject><subject>Dendritic Cells - metabolism</subject><subject>Diabetes Mellitus, Experimental - immunology</subject><subject>Diabetes Mellitus, Experimental - metabolism</subject><subject>Diabetes Mellitus, Type 1 - immunology</subject><subject>Diabetes Mellitus, Type 1 - metabolism</subject><subject>Female</subject><subject>Gastrointestinal Microbiome</subject><subject>Immunology</subject><subject>Interferon-gamma - metabolism</subject><subject>Internal Medicine</subject><subject>Male</subject><subject>Medical Microbiology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Inbred NOD</subject><subject>Mice, Knockout</subject><subject>Pancreas - immunology</subject><subject>Pancreas - metabolism</subject><subject>Pancreas - pathology</subject><subject>Pharmacology/Toxicology</subject><subject>Receptors, G-Protein-Coupled - deficiency</subject><subject>Receptors, G-Protein-Coupled - genetics</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Streptozocin</subject><subject>Suppressor of Cytokine Signaling 3 Protein - genetics</subject><subject>Suppressor of Cytokine Signaling 3 Protein - metabolism</subject><subject>Vaccine</subject><issn>1671-4083</issn><issn>1745-7254</issn><issn>1745-7254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE9PGzEQxS1U1ADtF-BQ-diLqf_t2nusUEuRkIoQnC2vdxw5ytrB9lYKnx6noT1ymhm9N08zP4QuGb1iVOhvRTJJGaFcEsq45ESdoDOmZEcU7-SH1veKEUm1WKHzUjaUCi7Y8BGthO6Y1D0_Q8839w-S4Ql8cAGi22O7Xmf7x1YouO53gJsY7AiHOURcaoZdTS-pJhciaVNzTngODvC4x7uc5lRDXLfEOOVQg8MOtls827pkW0OKn9Cpt9sCn9_qBXr6-ePx-he5-31ze_39jjg-6Eq8o7LXrtO9Fn7s_DTwVvQIwirhQY7eeq05VV7B1GQhvBMW-MCGQYiOiQv09ZjbbnpeoFQzh3K4xUZISzF8UJJSJmTfrPxodTmVksGbXQ6zzXvDqDmgNkfUpqE2f1Eb1Za-vOUv4wzT_5V_bJtBHA2lSXEN2WzSkmP7-b3YV-nUi40</recordid><startdate>20240701</startdate><enddate>20240701</enddate><creator>Li, Jia-hong</creator><creator>Zhang, Ming</creator><creator>Zhang, Zhao-di</creator><creator>Pan, Xiao-hua</creator><creator>Pan, Li-long</creator><creator>Sun, Jia</creator><general>Springer Nature Singapore</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></search><sort><creationdate>20240701</creationdate><title>GPR41 deficiency aggravates type 1 diabetes in streptozotocin-treated mice by promoting dendritic cell maturation</title><author>Li, Jia-hong ; Zhang, Ming ; Zhang, Zhao-di ; Pan, Xiao-hua ; Pan, Li-long ; Sun, Jia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c298t-fc0468c58683fb5fd92fb58be3a73fe4bfaf88207f7ed5fd33fc3ae2919933513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Dendritic Cells - immunology</topic><topic>Dendritic Cells - metabolism</topic><topic>Diabetes Mellitus, Experimental - immunology</topic><topic>Diabetes Mellitus, Experimental - metabolism</topic><topic>Diabetes Mellitus, Type 1 - immunology</topic><topic>Diabetes Mellitus, Type 1 - metabolism</topic><topic>Female</topic><topic>Gastrointestinal Microbiome</topic><topic>Immunology</topic><topic>Interferon-gamma - metabolism</topic><topic>Internal Medicine</topic><topic>Male</topic><topic>Medical Microbiology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Inbred NOD</topic><topic>Mice, Knockout</topic><topic>Pancreas - immunology</topic><topic>Pancreas - metabolism</topic><topic>Pancreas - pathology</topic><topic>Pharmacology/Toxicology</topic><topic>Receptors, G-Protein-Coupled - deficiency</topic><topic>Receptors, G-Protein-Coupled - genetics</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Streptozocin</topic><topic>Suppressor of Cytokine Signaling 3 Protein - genetics</topic><topic>Suppressor of Cytokine Signaling 3 Protein - metabolism</topic><topic>Vaccine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Jia-hong</creatorcontrib><creatorcontrib>Zhang, Ming</creatorcontrib><creatorcontrib>Zhang, Zhao-di</creatorcontrib><creatorcontrib>Pan, Xiao-hua</creatorcontrib><creatorcontrib>Pan, Li-long</creatorcontrib><creatorcontrib>Sun, Jia</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><jtitle>Acta pharmacologica Sinica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Jia-hong</au><au>Zhang, Ming</au><au>Zhang, Zhao-di</au><au>Pan, Xiao-hua</au><au>Pan, Li-long</au><au>Sun, Jia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>GPR41 deficiency aggravates type 1 diabetes in streptozotocin-treated mice by promoting dendritic cell maturation</atitle><jtitle>Acta pharmacologica Sinica</jtitle><stitle>Acta Pharmacol Sin</stitle><addtitle>Acta Pharmacol Sin</addtitle><date>2024-07-01</date><risdate>2024</risdate><volume>45</volume><issue>7</issue><spage>1466</spage><epage>1476</epage><pages>1466-1476</pages><issn>1671-4083</issn><issn>1745-7254</issn><eissn>1745-7254</eissn><abstract>Disturbances in intestinal immune homeostasis predispose susceptible individuals to type 1 diabetes (T1D). G-protein-coupled receptor 41 (GPR41) is a receptor for short-chain fatty acids (SCFAs) mainly produced by gut microbiota, which plays key roles in maintaining intestinal homeostasis. In this study, we investigated the role of GPR41 in the progression of T1D. In non-obese diabetic (NOD) mice, we found that aberrant reduction of GPR41 expression in the pancreas and colons was associated with the development of T1D. GPR41-deficient (
Gpr41
−/−
) mice displayed significantly exacerbated streptozotocin (STZ)-induced T1D compared to wild-type mice. Furthermore,
Gpr41
−/−
mice showed enhanced gut immune dysregulation and increased migration of gut-primed IFN-γ
+
T cells to the pancreas. In bone marrow-derived dendritic cells from
Gpr41
−/−
mice, the expression of suppressor of cytokine signaling 3 (SOCS) was significantly inhibited, while the phosphorylation of STAT3 was significantly increased, thus promoting dendritic cell (DC) maturation. Furthermore, adoptive transfer of bone marrow-derived dendritic cells (BMDC) from
Gpr41
−/−
mice accelerated T1D in irradiated NOD mice. We conclude that GPR41 is essential for maintaining intestinal and pancreatic immune homeostasis and acts as a negative regulator of DC maturation in T1D. GPR41 may be a potential therapeutic target for T1D.</abstract><cop>Singapore</cop><pub>Springer Nature Singapore</pub><pmid>38514862</pmid><doi>10.1038/s41401-024-01242-7</doi><tpages>11</tpages></addata></record> |
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| subjects | Animals Biomedical and Life Sciences Biomedicine Dendritic Cells - immunology Dendritic Cells - metabolism Diabetes Mellitus, Experimental - immunology Diabetes Mellitus, Experimental - metabolism Diabetes Mellitus, Type 1 - immunology Diabetes Mellitus, Type 1 - metabolism Female Gastrointestinal Microbiome Immunology Interferon-gamma - metabolism Internal Medicine Male Medical Microbiology Mice Mice, Inbred C57BL Mice, Inbred NOD Mice, Knockout Pancreas - immunology Pancreas - metabolism Pancreas - pathology Pharmacology/Toxicology Receptors, G-Protein-Coupled - deficiency Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism STAT3 Transcription Factor - metabolism Streptozocin Suppressor of Cytokine Signaling 3 Protein - genetics Suppressor of Cytokine Signaling 3 Protein - metabolism Vaccine |
| title | GPR41 deficiency aggravates type 1 diabetes in streptozotocin-treated mice by promoting dendritic cell maturation |
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