Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation
Resident and inflammatory mononuclear phagocytes (MPh) with functional plasticity in the intestine are critically involved in the pathology of Inflammatory Bowel Diseases (IBD), in which the mechanism remains incompletely understood. In the present study, we found that increased expression of E3 lig...
Gespeichert in:
| Veröffentlicht in: | The Journal of clinical investigation 2019-08, Vol.130 (9), p.3877-3893 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 3893 |
|---|---|
| container_issue | 9 |
| container_start_page | 3877 |
| container_title | The Journal of clinical investigation |
| container_volume | 130 |
| creator | He, Jia Song, Yinjing Li, Gaopeng Xiao, Peng Liu, Yang Xue, Yue Cao, Qian Tu, Xintao Pan, Ting Jiang, Zhinong Cao, Xuetao Lai, Lihua Wang, Qingqing |
| description | Resident and inflammatory mononuclear phagocytes (MPh) with functional plasticity in the intestine are critically involved in the pathology of Inflammatory Bowel Diseases (IBD), in which the mechanism remains incompletely understood. In the present study, we found that increased expression of E3 ligase FBXW7 in the inflamed intestine was significantly correlated to IBD severity in both human diseases and mice model. Myeloid-Fbxw7 deficiency protected mice from dextran sodium sulfate (DSS) and 2,6,4-trinitrobenzene sulfonic acid (TNBS) induced colitis. Fbxw7 deficiency resulted in decreased production of chemokines CCL2 and CCL7 by colonic CX3CR1hi resident macrophages and reduced accumulation of CX3CR1int pro-inflammatory MPh in colitis colon tissue. Mice received AAV-shFbxw7 administration showed significantly improved survival rate and alleviated colitis. Mechanisms screening demonstrated that FBXW7 suppresses H3K27me3 modification and promotes Ccl2 and Ccl7 expression via degradation of histone-lysine N-methyltransferase EZH2 in macrophages. Taken together, our results indicate that FBXW7 degrades EZH2 and increases Ccl2/Ccl7 in CX3CR1hi macrophages, which promotes the recruiting CX3CR1int pro-inflammatory MPh into local colon tissues with colitis. Targeting FBXW7 might represent a potential therapeutic approach for intestine inflammation intervention. |
| doi_str_mv | 10.1172/JCI123374 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6715366</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2288674098</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3544-7fdb24a920fea873cb33576dc32c664147c0623d7ca097b92268872290c456623</originalsourceid><addsrcrecordid>eNpdkU1LAzEQhoMotlYP_gFZ8KKHtflO9iLIYrVSEEXBW8im2XZld1OTrR__3pTWop5mmPfhZWZeAI4RvEBI4OFdPkaYEEF3QB8xJlOJidwFfQgxSjNBZA8chPAKIaKU0X3QIwhTziTqg4dR8fkhkqo13upgQ5LnEzxcDZL8heSPaF4ljTbeLeZ6FuXOJQvvGtfZiHQ2dFWr69iWtW4a3VWuPQR7pa6DPdrUAXgeXT_lt-nk_macX01SQxilqSinBaY6w7C0WgpiCkKY4FNDsOGcIioM5JhMhdEwE0WGMZdSYJxBQxmPygBcrn0Xy6KxU2PbzutaLXzVaP-lnK7UX6Wt5mrm3hUXiBHOo8HZxsC7t2U8RTVVMLaudWvdMiiMGeSUk_jZATj9h766pY-XrygpuaAwk5E6X1PxXSF4W26XQVCtglLboCJ78nv7LfmTDPkGoamLKg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2288674098</pqid></control><display><type>article</type><title>Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation</title><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>He, Jia ; Song, Yinjing ; Li, Gaopeng ; Xiao, Peng ; Liu, Yang ; Xue, Yue ; Cao, Qian ; Tu, Xintao ; Pan, Ting ; Jiang, Zhinong ; Cao, Xuetao ; Lai, Lihua ; Wang, Qingqing</creator><creatorcontrib>He, Jia ; Song, Yinjing ; Li, Gaopeng ; Xiao, Peng ; Liu, Yang ; Xue, Yue ; Cao, Qian ; Tu, Xintao ; Pan, Ting ; Jiang, Zhinong ; Cao, Xuetao ; Lai, Lihua ; Wang, Qingqing</creatorcontrib><description>Resident and inflammatory mononuclear phagocytes (MPh) with functional plasticity in the intestine are critically involved in the pathology of Inflammatory Bowel Diseases (IBD), in which the mechanism remains incompletely understood. In the present study, we found that increased expression of E3 ligase FBXW7 in the inflamed intestine was significantly correlated to IBD severity in both human diseases and mice model. Myeloid-Fbxw7 deficiency protected mice from dextran sodium sulfate (DSS) and 2,6,4-trinitrobenzene sulfonic acid (TNBS) induced colitis. Fbxw7 deficiency resulted in decreased production of chemokines CCL2 and CCL7 by colonic CX3CR1hi resident macrophages and reduced accumulation of CX3CR1int pro-inflammatory MPh in colitis colon tissue. Mice received AAV-shFbxw7 administration showed significantly improved survival rate and alleviated colitis. Mechanisms screening demonstrated that FBXW7 suppresses H3K27me3 modification and promotes Ccl2 and Ccl7 expression via degradation of histone-lysine N-methyltransferase EZH2 in macrophages. Taken together, our results indicate that FBXW7 degrades EZH2 and increases Ccl2/Ccl7 in CX3CR1hi macrophages, which promotes the recruiting CX3CR1int pro-inflammatory MPh into local colon tissues with colitis. Targeting FBXW7 might represent a potential therapeutic approach for intestine inflammation intervention.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI123374</identifier><identifier>PMID: 31246581</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Animal models ; Apoptosis ; Biomedical research ; Cdc4 protein ; Chemokines ; Colitis ; Colon ; Crohn's disease ; Dextran ; Epigenetics ; Functional plasticity ; Gastroenterology ; Gene expression ; Histone-lysine N-methyltransferase ; Inflammation ; Inflammatory bowel disease ; Inflammatory bowel diseases ; Intestine ; Kinases ; Leukocytes (mononuclear) ; Lysine ; Macrophages ; Methyltransferase ; Monocyte chemoattractant protein 1 ; N-Methyltransferase ; Pathogenesis ; Phagocytes ; Sodium ; Sodium sulfate ; Sulfonic acid ; Ubiquitin-protein ligase</subject><ispartof>The Journal of clinical investigation, 2019-08, Vol.130 (9), p.3877-3893</ispartof><rights>Copyright American Society for Clinical Investigation Sep 2019</rights><rights>2019 American Society for Clinical Investigation 2019 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3544-7fdb24a920fea873cb33576dc32c664147c0623d7ca097b92268872290c456623</citedby><cites>FETCH-LOGICAL-c3544-7fdb24a920fea873cb33576dc32c664147c0623d7ca097b92268872290c456623</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715366/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715366/$$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/31246581$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>He, Jia</creatorcontrib><creatorcontrib>Song, Yinjing</creatorcontrib><creatorcontrib>Li, Gaopeng</creatorcontrib><creatorcontrib>Xiao, Peng</creatorcontrib><creatorcontrib>Liu, Yang</creatorcontrib><creatorcontrib>Xue, Yue</creatorcontrib><creatorcontrib>Cao, Qian</creatorcontrib><creatorcontrib>Tu, Xintao</creatorcontrib><creatorcontrib>Pan, Ting</creatorcontrib><creatorcontrib>Jiang, Zhinong</creatorcontrib><creatorcontrib>Cao, Xuetao</creatorcontrib><creatorcontrib>Lai, Lihua</creatorcontrib><creatorcontrib>Wang, Qingqing</creatorcontrib><title>Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Resident and inflammatory mononuclear phagocytes (MPh) with functional plasticity in the intestine are critically involved in the pathology of Inflammatory Bowel Diseases (IBD), in which the mechanism remains incompletely understood. In the present study, we found that increased expression of E3 ligase FBXW7 in the inflamed intestine was significantly correlated to IBD severity in both human diseases and mice model. Myeloid-Fbxw7 deficiency protected mice from dextran sodium sulfate (DSS) and 2,6,4-trinitrobenzene sulfonic acid (TNBS) induced colitis. Fbxw7 deficiency resulted in decreased production of chemokines CCL2 and CCL7 by colonic CX3CR1hi resident macrophages and reduced accumulation of CX3CR1int pro-inflammatory MPh in colitis colon tissue. Mice received AAV-shFbxw7 administration showed significantly improved survival rate and alleviated colitis. Mechanisms screening demonstrated that FBXW7 suppresses H3K27me3 modification and promotes Ccl2 and Ccl7 expression via degradation of histone-lysine N-methyltransferase EZH2 in macrophages. Taken together, our results indicate that FBXW7 degrades EZH2 and increases Ccl2/Ccl7 in CX3CR1hi macrophages, which promotes the recruiting CX3CR1int pro-inflammatory MPh into local colon tissues with colitis. Targeting FBXW7 might represent a potential therapeutic approach for intestine inflammation intervention.</description><subject>Animal models</subject><subject>Apoptosis</subject><subject>Biomedical research</subject><subject>Cdc4 protein</subject><subject>Chemokines</subject><subject>Colitis</subject><subject>Colon</subject><subject>Crohn's disease</subject><subject>Dextran</subject><subject>Epigenetics</subject><subject>Functional plasticity</subject><subject>Gastroenterology</subject><subject>Gene expression</subject><subject>Histone-lysine N-methyltransferase</subject><subject>Inflammation</subject><subject>Inflammatory bowel disease</subject><subject>Inflammatory bowel diseases</subject><subject>Intestine</subject><subject>Kinases</subject><subject>Leukocytes (mononuclear)</subject><subject>Lysine</subject><subject>Macrophages</subject><subject>Methyltransferase</subject><subject>Monocyte chemoattractant protein 1</subject><subject>N-Methyltransferase</subject><subject>Pathogenesis</subject><subject>Phagocytes</subject><subject>Sodium</subject><subject>Sodium sulfate</subject><subject>Sulfonic acid</subject><subject>Ubiquitin-protein ligase</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><recordid>eNpdkU1LAzEQhoMotlYP_gFZ8KKHtflO9iLIYrVSEEXBW8im2XZld1OTrR__3pTWop5mmPfhZWZeAI4RvEBI4OFdPkaYEEF3QB8xJlOJidwFfQgxSjNBZA8chPAKIaKU0X3QIwhTziTqg4dR8fkhkqo13upgQ5LnEzxcDZL8heSPaF4ljTbeLeZ6FuXOJQvvGtfZiHQ2dFWr69iWtW4a3VWuPQR7pa6DPdrUAXgeXT_lt-nk_macX01SQxilqSinBaY6w7C0WgpiCkKY4FNDsOGcIioM5JhMhdEwE0WGMZdSYJxBQxmPygBcrn0Xy6KxU2PbzutaLXzVaP-lnK7UX6Wt5mrm3hUXiBHOo8HZxsC7t2U8RTVVMLaudWvdMiiMGeSUk_jZATj9h766pY-XrygpuaAwk5E6X1PxXSF4W26XQVCtglLboCJ78nv7LfmTDPkGoamLKg</recordid><startdate>20190819</startdate><enddate>20190819</enddate><creator>He, Jia</creator><creator>Song, Yinjing</creator><creator>Li, Gaopeng</creator><creator>Xiao, Peng</creator><creator>Liu, Yang</creator><creator>Xue, Yue</creator><creator>Cao, Qian</creator><creator>Tu, Xintao</creator><creator>Pan, Ting</creator><creator>Jiang, Zhinong</creator><creator>Cao, Xuetao</creator><creator>Lai, Lihua</creator><creator>Wang, Qingqing</creator><general>American Society for Clinical Investigation</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20190819</creationdate><title>Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation</title><author>He, Jia ; Song, Yinjing ; Li, Gaopeng ; Xiao, Peng ; Liu, Yang ; Xue, Yue ; Cao, Qian ; Tu, Xintao ; Pan, Ting ; Jiang, Zhinong ; Cao, Xuetao ; Lai, Lihua ; Wang, Qingqing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3544-7fdb24a920fea873cb33576dc32c664147c0623d7ca097b92268872290c456623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animal models</topic><topic>Apoptosis</topic><topic>Biomedical research</topic><topic>Cdc4 protein</topic><topic>Chemokines</topic><topic>Colitis</topic><topic>Colon</topic><topic>Crohn's disease</topic><topic>Dextran</topic><topic>Epigenetics</topic><topic>Functional plasticity</topic><topic>Gastroenterology</topic><topic>Gene expression</topic><topic>Histone-lysine N-methyltransferase</topic><topic>Inflammation</topic><topic>Inflammatory bowel disease</topic><topic>Inflammatory bowel diseases</topic><topic>Intestine</topic><topic>Kinases</topic><topic>Leukocytes (mononuclear)</topic><topic>Lysine</topic><topic>Macrophages</topic><topic>Methyltransferase</topic><topic>Monocyte chemoattractant protein 1</topic><topic>N-Methyltransferase</topic><topic>Pathogenesis</topic><topic>Phagocytes</topic><topic>Sodium</topic><topic>Sodium sulfate</topic><topic>Sulfonic acid</topic><topic>Ubiquitin-protein ligase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>He, Jia</creatorcontrib><creatorcontrib>Song, Yinjing</creatorcontrib><creatorcontrib>Li, Gaopeng</creatorcontrib><creatorcontrib>Xiao, Peng</creatorcontrib><creatorcontrib>Liu, Yang</creatorcontrib><creatorcontrib>Xue, Yue</creatorcontrib><creatorcontrib>Cao, Qian</creatorcontrib><creatorcontrib>Tu, Xintao</creatorcontrib><creatorcontrib>Pan, Ting</creatorcontrib><creatorcontrib>Jiang, Zhinong</creatorcontrib><creatorcontrib>Cao, Xuetao</creatorcontrib><creatorcontrib>Lai, Lihua</creatorcontrib><creatorcontrib>Wang, Qingqing</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>He, Jia</au><au>Song, Yinjing</au><au>Li, Gaopeng</au><au>Xiao, Peng</au><au>Liu, Yang</au><au>Xue, Yue</au><au>Cao, Qian</au><au>Tu, Xintao</au><au>Pan, Ting</au><au>Jiang, Zhinong</au><au>Cao, Xuetao</au><au>Lai, Lihua</au><au>Wang, Qingqing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2019-08-19</date><risdate>2019</risdate><volume>130</volume><issue>9</issue><spage>3877</spage><epage>3893</epage><pages>3877-3893</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>Resident and inflammatory mononuclear phagocytes (MPh) with functional plasticity in the intestine are critically involved in the pathology of Inflammatory Bowel Diseases (IBD), in which the mechanism remains incompletely understood. In the present study, we found that increased expression of E3 ligase FBXW7 in the inflamed intestine was significantly correlated to IBD severity in both human diseases and mice model. Myeloid-Fbxw7 deficiency protected mice from dextran sodium sulfate (DSS) and 2,6,4-trinitrobenzene sulfonic acid (TNBS) induced colitis. Fbxw7 deficiency resulted in decreased production of chemokines CCL2 and CCL7 by colonic CX3CR1hi resident macrophages and reduced accumulation of CX3CR1int pro-inflammatory MPh in colitis colon tissue. Mice received AAV-shFbxw7 administration showed significantly improved survival rate and alleviated colitis. Mechanisms screening demonstrated that FBXW7 suppresses H3K27me3 modification and promotes Ccl2 and Ccl7 expression via degradation of histone-lysine N-methyltransferase EZH2 in macrophages. Taken together, our results indicate that FBXW7 degrades EZH2 and increases Ccl2/Ccl7 in CX3CR1hi macrophages, which promotes the recruiting CX3CR1int pro-inflammatory MPh into local colon tissues with colitis. Targeting FBXW7 might represent a potential therapeutic approach for intestine inflammation intervention.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>31246581</pmid><doi>10.1172/JCI123374</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-9738 |
| ispartof | The Journal of clinical investigation, 2019-08, Vol.130 (9), p.3877-3893 |
| issn | 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6715366 |
| source | EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Animal models Apoptosis Biomedical research Cdc4 protein Chemokines Colitis Colon Crohn's disease Dextran Epigenetics Functional plasticity Gastroenterology Gene expression Histone-lysine N-methyltransferase Inflammation Inflammatory bowel disease Inflammatory bowel diseases Intestine Kinases Leukocytes (mononuclear) Lysine Macrophages Methyltransferase Monocyte chemoattractant protein 1 N-Methyltransferase Pathogenesis Phagocytes Sodium Sodium sulfate Sulfonic acid Ubiquitin-protein ligase |
| title | Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T07%3A41%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Fbxw7%20increases%20CCL2/7%20in%20CX3CR1hi%20macrophages%20to%20promote%20intestinal%20inflammation&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=He,%20Jia&rft.date=2019-08-19&rft.volume=130&rft.issue=9&rft.spage=3877&rft.epage=3893&rft.pages=3877-3893&rft.issn=0021-9738&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI123374&rft_dat=%3Cproquest_pubme%3E2288674098%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2288674098&rft_id=info:pmid/31246581&rfr_iscdi=true |