Regulation of Monocyte Activation by PPARα Through Interaction With the cGAS-STING Pathway
Monocyte activation plays an important role in diabetic complications such as diabetic retinopathy (DR). However, the regulation of monocyte activation in diabetes remains elusive. Fenofibrate, an agonist of peroxisome proliferator-activated receptor-α (PPARα), has shown robust therapeutic effects o...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2023-07, Vol.72 (7), p.958-972 |
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| container_title | Diabetes (New York, N.Y.) |
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| creator | Dong, Lijie Cheng, Rui Ma, Xiang Liang, Wentao Hong, Yaru Li, Hui Zhou, Kelu Du, Yanhong Takahashi, Yusuke Zhang, Xiaomin Li, Xiao-Rong Ma, Jian-Xing |
| description | Monocyte activation plays an important role in diabetic complications such as diabetic retinopathy (DR). However, the regulation of monocyte activation in diabetes remains elusive. Fenofibrate, an agonist of peroxisome proliferator-activated receptor-α (PPARα), has shown robust therapeutic effects on DR in patients with type 2 diabetes. Here we found that PPARα levels were significantly downregulated in monocytes from patients with diabetes and animal models, correlating with monocyte activation. Fenofibrate attenuated monocyte activation in diabetes, while PPARα knockout alone induced monocyte activation. Furthermore, monocyte-specific PPARα overexpression ameliorated, while monocyte-specific PPARα knockout aggravated monocyte activation in diabetes. PPARα knockout impaired mitochondrial function while also increasing glycolysis in monocytes. PPARα knockout increased cytosolic mitochondrial DNA release and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in monocytes under diabetic conditions. STING knockout or STING inhibitor attenuated monocyte activation induced by diabetes or by PPARα knockout. These observations suggest that PPARα negatively regulates monocyte activation through metabolic reprogramming and interaction with the cGAS-STING pathway. |
| doi_str_mv | 10.2337/db22-0654 |
| format | Article |
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However, the regulation of monocyte activation in diabetes remains elusive. Fenofibrate, an agonist of peroxisome proliferator-activated receptor-α (PPARα), has shown robust therapeutic effects on DR in patients with type 2 diabetes. Here we found that PPARα levels were significantly downregulated in monocytes from patients with diabetes and animal models, correlating with monocyte activation. Fenofibrate attenuated monocyte activation in diabetes, while PPARα knockout alone induced monocyte activation. Furthermore, monocyte-specific PPARα overexpression ameliorated, while monocyte-specific PPARα knockout aggravated monocyte activation in diabetes. PPARα knockout impaired mitochondrial function while also increasing glycolysis in monocytes. PPARα knockout increased cytosolic mitochondrial DNA release and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in monocytes under diabetic conditions. STING knockout or STING inhibitor attenuated monocyte activation induced by diabetes or by PPARα knockout. These observations suggest that PPARα negatively regulates monocyte activation through metabolic reprogramming and interaction with the cGAS-STING pathway.</description><identifier>ISSN: 0012-1797</identifier><identifier>ISSN: 1939-327X</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db22-0654</identifier><identifier>PMID: 37058417</identifier><language>eng</language><publisher>United States: American Diabetes Association</publisher><subject>Animal models ; Animals ; Cell activation ; Complications ; Diabetes ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus, Type 2 - genetics ; Diabetes Mellitus, Type 2 - metabolism ; Diabetic Retinopathy - metabolism ; Down-regulation ; Fenofibrate ; Fenofibrate - pharmacology ; Fenofibrate - therapeutic use ; Glycolysis ; Metabolic rate ; Mitochondrial DNA ; Monocytes ; Monocytes - metabolism ; Nucleotidyltransferases - genetics ; Nucleotidyltransferases - metabolism ; Peroxisome proliferator-activated receptors ; PPAR alpha - genetics ; PPAR alpha - metabolism ; Retinopathy</subject><ispartof>Diabetes (New York, N.Y.), 2023-07, Vol.72 (7), p.958-972</ispartof><rights>2023 by the American Diabetes Association.</rights><rights>Copyright American Diabetes Association Jul 2023</rights><rights>2023 by the American Diabetes Association 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c404t-28635e976c71ec3d0b45066172268ac038a7710b458344801652d6bffbd7d94e3</citedby><cites>FETCH-LOGICAL-c404t-28635e976c71ec3d0b45066172268ac038a7710b458344801652d6bffbd7d94e3</cites><orcidid>0000-0003-0641-2797 ; 0000-0001-8815-1716</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/PMC10281240/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10281240/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27922,27923,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37058417$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dong, Lijie</creatorcontrib><creatorcontrib>Cheng, Rui</creatorcontrib><creatorcontrib>Ma, Xiang</creatorcontrib><creatorcontrib>Liang, Wentao</creatorcontrib><creatorcontrib>Hong, Yaru</creatorcontrib><creatorcontrib>Li, Hui</creatorcontrib><creatorcontrib>Zhou, Kelu</creatorcontrib><creatorcontrib>Du, Yanhong</creatorcontrib><creatorcontrib>Takahashi, Yusuke</creatorcontrib><creatorcontrib>Zhang, Xiaomin</creatorcontrib><creatorcontrib>Li, Xiao-Rong</creatorcontrib><creatorcontrib>Ma, Jian-Xing</creatorcontrib><title>Regulation of Monocyte Activation by PPARα Through Interaction With the cGAS-STING Pathway</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Monocyte activation plays an important role in diabetic complications such as diabetic retinopathy (DR). However, the regulation of monocyte activation in diabetes remains elusive. Fenofibrate, an agonist of peroxisome proliferator-activated receptor-α (PPARα), has shown robust therapeutic effects on DR in patients with type 2 diabetes. Here we found that PPARα levels were significantly downregulated in monocytes from patients with diabetes and animal models, correlating with monocyte activation. Fenofibrate attenuated monocyte activation in diabetes, while PPARα knockout alone induced monocyte activation. Furthermore, monocyte-specific PPARα overexpression ameliorated, while monocyte-specific PPARα knockout aggravated monocyte activation in diabetes. PPARα knockout impaired mitochondrial function while also increasing glycolysis in monocytes. PPARα knockout increased cytosolic mitochondrial DNA release and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in monocytes under diabetic conditions. STING knockout or STING inhibitor attenuated monocyte activation induced by diabetes or by PPARα knockout. These observations suggest that PPARα negatively regulates monocyte activation through metabolic reprogramming and interaction with the cGAS-STING pathway.</description><subject>Animal models</subject><subject>Animals</subject><subject>Cell activation</subject><subject>Complications</subject><subject>Diabetes</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Diabetes Mellitus, Type 2 - genetics</subject><subject>Diabetes Mellitus, Type 2 - metabolism</subject><subject>Diabetic Retinopathy - metabolism</subject><subject>Down-regulation</subject><subject>Fenofibrate</subject><subject>Fenofibrate - pharmacology</subject><subject>Fenofibrate - therapeutic use</subject><subject>Glycolysis</subject><subject>Metabolic rate</subject><subject>Mitochondrial DNA</subject><subject>Monocytes</subject><subject>Monocytes - metabolism</subject><subject>Nucleotidyltransferases - genetics</subject><subject>Nucleotidyltransferases - metabolism</subject><subject>Peroxisome proliferator-activated receptors</subject><subject>PPAR alpha - genetics</subject><subject>PPAR alpha - metabolism</subject><subject>Retinopathy</subject><issn>0012-1797</issn><issn>1939-327X</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc9u1DAQxi1ERZfSAy-ALHGhh7TjP7GdE1pVdLtSoat2K5A4WI7jbFJl49Zxivax-iI8E162VIDmMNLMT998ow-htwSOKWPypCopzUDk_AWakIIVGaPy20s0ASA0I7KQ--j1MNwCgEj1Cu0zCbniRE7Q9yu3GjsTW99jX-PPvvd2Ex2e2tg-7MblBi8W06ufj3jZBD-uGjzvowvG_t5-bWODY-OwnU2vs-vl_MsML0xsfpjNG7RXm25wh0_9AN2cfVqenmcXl7P56fQisxx4zKgSLHeFFFYSZ1kFJc9BCCIpFcpYYMpISbZTxThXQEROK1HWdVnJquCOHaCPO927sVy7yro-BtPpu9CuTdhob1r976ZvG73yD5oAVYRySAofnhSCvx_dEPW6HazrOtM7Pw6apquFVFCQhL7_D731Y-jTf4miKhGFkIk62lE2-GEIrn52Q0BvM9PbzPQ2s8S--9v-M_knJPYLa7-Qfg</recordid><startdate>20230701</startdate><enddate>20230701</enddate><creator>Dong, Lijie</creator><creator>Cheng, Rui</creator><creator>Ma, Xiang</creator><creator>Liang, Wentao</creator><creator>Hong, Yaru</creator><creator>Li, Hui</creator><creator>Zhou, Kelu</creator><creator>Du, Yanhong</creator><creator>Takahashi, Yusuke</creator><creator>Zhang, Xiaomin</creator><creator>Li, Xiao-Rong</creator><creator>Ma, Jian-Xing</creator><general>American Diabetes Association</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>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0641-2797</orcidid><orcidid>https://orcid.org/0000-0001-8815-1716</orcidid></search><sort><creationdate>20230701</creationdate><title>Regulation of Monocyte Activation by PPARα Through Interaction With the cGAS-STING Pathway</title><author>Dong, Lijie ; Cheng, Rui ; Ma, Xiang ; Liang, Wentao ; Hong, Yaru ; Li, Hui ; Zhou, Kelu ; Du, Yanhong ; Takahashi, Yusuke ; Zhang, Xiaomin ; Li, Xiao-Rong ; Ma, Jian-Xing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c404t-28635e976c71ec3d0b45066172268ac038a7710b458344801652d6bffbd7d94e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Cell activation</topic><topic>Complications</topic><topic>Diabetes</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Diabetes Mellitus, Type 2 - genetics</topic><topic>Diabetes Mellitus, Type 2 - metabolism</topic><topic>Diabetic Retinopathy - metabolism</topic><topic>Down-regulation</topic><topic>Fenofibrate</topic><topic>Fenofibrate - pharmacology</topic><topic>Fenofibrate - therapeutic use</topic><topic>Glycolysis</topic><topic>Metabolic rate</topic><topic>Mitochondrial DNA</topic><topic>Monocytes</topic><topic>Monocytes - metabolism</topic><topic>Nucleotidyltransferases - genetics</topic><topic>Nucleotidyltransferases - metabolism</topic><topic>Peroxisome proliferator-activated receptors</topic><topic>PPAR alpha - genetics</topic><topic>PPAR alpha - metabolism</topic><topic>Retinopathy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dong, Lijie</creatorcontrib><creatorcontrib>Cheng, Rui</creatorcontrib><creatorcontrib>Ma, Xiang</creatorcontrib><creatorcontrib>Liang, Wentao</creatorcontrib><creatorcontrib>Hong, Yaru</creatorcontrib><creatorcontrib>Li, Hui</creatorcontrib><creatorcontrib>Zhou, Kelu</creatorcontrib><creatorcontrib>Du, Yanhong</creatorcontrib><creatorcontrib>Takahashi, Yusuke</creatorcontrib><creatorcontrib>Zhang, Xiaomin</creatorcontrib><creatorcontrib>Li, Xiao-Rong</creatorcontrib><creatorcontrib>Ma, Jian-Xing</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dong, Lijie</au><au>Cheng, Rui</au><au>Ma, Xiang</au><au>Liang, Wentao</au><au>Hong, Yaru</au><au>Li, Hui</au><au>Zhou, Kelu</au><au>Du, Yanhong</au><au>Takahashi, Yusuke</au><au>Zhang, Xiaomin</au><au>Li, Xiao-Rong</au><au>Ma, Jian-Xing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulation of Monocyte Activation by PPARα Through Interaction With the cGAS-STING Pathway</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2023-07-01</date><risdate>2023</risdate><volume>72</volume><issue>7</issue><spage>958</spage><epage>972</epage><pages>958-972</pages><issn>0012-1797</issn><issn>1939-327X</issn><eissn>1939-327X</eissn><abstract>Monocyte activation plays an important role in diabetic complications such as diabetic retinopathy (DR). However, the regulation of monocyte activation in diabetes remains elusive. Fenofibrate, an agonist of peroxisome proliferator-activated receptor-α (PPARα), has shown robust therapeutic effects on DR in patients with type 2 diabetes. Here we found that PPARα levels were significantly downregulated in monocytes from patients with diabetes and animal models, correlating with monocyte activation. Fenofibrate attenuated monocyte activation in diabetes, while PPARα knockout alone induced monocyte activation. Furthermore, monocyte-specific PPARα overexpression ameliorated, while monocyte-specific PPARα knockout aggravated monocyte activation in diabetes. PPARα knockout impaired mitochondrial function while also increasing glycolysis in monocytes. PPARα knockout increased cytosolic mitochondrial DNA release and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in monocytes under diabetic conditions. STING knockout or STING inhibitor attenuated monocyte activation induced by diabetes or by PPARα knockout. These observations suggest that PPARα negatively regulates monocyte activation through metabolic reprogramming and interaction with the cGAS-STING pathway.</abstract><cop>United States</cop><pub>American Diabetes Association</pub><pmid>37058417</pmid><doi>10.2337/db22-0654</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0003-0641-2797</orcidid><orcidid>https://orcid.org/0000-0001-8815-1716</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animal models Animals Cell activation Complications Diabetes Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - genetics Diabetes Mellitus, Type 2 - metabolism Diabetic Retinopathy - metabolism Down-regulation Fenofibrate Fenofibrate - pharmacology Fenofibrate - therapeutic use Glycolysis Metabolic rate Mitochondrial DNA Monocytes Monocytes - metabolism Nucleotidyltransferases - genetics Nucleotidyltransferases - metabolism Peroxisome proliferator-activated receptors PPAR alpha - genetics PPAR alpha - metabolism Retinopathy |
| title | Regulation of Monocyte Activation by PPARα Through Interaction With the cGAS-STING Pathway |
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