JCI insight最新文献

筛选
英文 中文
Sphingosine-1-phosphate (S1P) receptor type 1 signaling in macrophages reduces atherosclerosis in LDL receptor-deficient mice. 巨噬细胞中的球蛋白-1-磷酸(S1P)受体 1 型信号可减少低密度脂蛋白受体缺陷小鼠的动脉粥样硬化。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-12 DOI: 10.1172/jci.insight.158127
Francesco Potì, Enrica Scalera, Renata Feuerborn, Josephine Fischer, Lilli Arndt, Georg Varga, Evangelia Pardali, Matthias D Seidl, Manfred Fobker, Gerhard Liebisch, Bettina Hesse, Alexander H Lukasz, Jan Rossaint, Beate E Kehrel, Frank Rosenbauer, Thomas Renné, Christina Christoffersen, Manuela Simoni, Ralph Burkhardt, Jerzy-Roch Nofer
{"title":"Sphingosine-1-phosphate (S1P) receptor type 1 signaling in macrophages reduces atherosclerosis in LDL receptor-deficient mice.","authors":"Francesco Potì, Enrica Scalera, Renata Feuerborn, Josephine Fischer, Lilli Arndt, Georg Varga, Evangelia Pardali, Matthias D Seidl, Manfred Fobker, Gerhard Liebisch, Bettina Hesse, Alexander H Lukasz, Jan Rossaint, Beate E Kehrel, Frank Rosenbauer, Thomas Renné, Christina Christoffersen, Manuela Simoni, Ralph Burkhardt, Jerzy-Roch Nofer","doi":"10.1172/jci.insight.158127","DOIUrl":"https://doi.org/10.1172/jci.insight.158127","url":null,"abstract":"<p><p>Sphingosine 1-phosphate (S1P) is a lysosphingolipid with anti-atherogenic properties, but mechanisms underlying its effects remain unclear. We here investigated atherosclerosis development in cholesterol-rich diet-fed LDL receptor-deficient mice with high or low overexpression levels of S1P receptor type 1 (S1P1) in macrophages. S1P1-overexpressing macrophages showed increased activity of transcription factors PU.1, IRF8, and LXR and were skewed towards a M2-distinct phenotype characterized by enhanced production of IL-10, IL-1RA, and IL-5, increased ATP-binding cassette transporter A1- and G1-dependent cholesterol efflux, increased expression of MerTK and efferocytosis, and reduced apoptosis due to elevated Bcl6 and MafB. A similar macrophage phenotype was observed in mice administered S1P1-selective agonist KRP203. Mechanistically, the enhanced PU.1, IRF8, and LXR activity in S1P1-overexpressing macrophages led to down-regulation of the cAMP-dependent protein kinase A and activation of the signaling cascade encompassing protein kinases Akt and mTOR complex 1 (mTORC1) as well as the late endosomal/lysosomal adaptor MAPK and mTOR activator 1 (Lamtor-1). Atherosclerotic lesions in aortic roots and brachiocephalic arteries were profoundly or moderately reduced in mice with high and low S1P1 overexpression in macrophages, respectively. We conclude that S1P1 signaling polarizes macrophages towards an anti-atherogenic functional phenotype and countervails the development of atherosclerosis in mice.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
PCYT2 inhibits epithelial-to-mesenchymal transition in colorectal cancer by elevating YAP1 phosphorylation. PCYT2 通过提高 YAP1 磷酸化抑制结直肠癌上皮细胞向间质转化。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-12 DOI: 10.1172/jci.insight.178823
Lian Zhou, Su Zhang, Lingli Wang, Xueqin Liu, Xuyang Yang, Lei Qiu, Ying Zhou, Qing Huang, Yang Meng, Xue Lei, Linda Wen, Junhong Han
{"title":"PCYT2 inhibits epithelial-to-mesenchymal transition in colorectal cancer by elevating YAP1 phosphorylation.","authors":"Lian Zhou, Su Zhang, Lingli Wang, Xueqin Liu, Xuyang Yang, Lei Qiu, Ying Zhou, Qing Huang, Yang Meng, Xue Lei, Linda Wen, Junhong Han","doi":"10.1172/jci.insight.178823","DOIUrl":"https://doi.org/10.1172/jci.insight.178823","url":null,"abstract":"<p><p>Metabolic reprogramming is a common feature in tumor progression and metastasis. Like proteins, lipids can transduce signals through lipid-protein interactions. During tumor initiation and metastasis, dysregulation of the Hippo pathway plays a critical role. Specifically, the inhibition of YAP1 phosphorylation leads to the relocation of YAP1 to the nucleus to activate transcription of genes involved in metastasis. Although recent studies reveal the involvement of phosphatidylethanolamine (PE) synthesis enzyme phosphoethanolamine cytidylyltransferase 2 (PCYT2) in tumor chemoresistance, the impact of PCYT2 on tumor metastasis remains elusive. Here, we showed that PCYT2 was significantly downregulated in metastatic colorectal cancer (CRC) and acted as a tumor metastasis suppressor. Mechanistically, PCYT2 increased the interaction between PEBP1 and YAP1-phosphatase PPP2R1A, thus disrupting PPP2R1A-YAP1 association. As a result, phosphorylated-YAP1 levels were increased, leading to YAP1 degradation through the ubiquitin protease pathway. YAP1 reduction in the nucleus repressed the transcription of ZEB1 and Snail2, eventually resulting in metastasis suppression. Our work provides insight into the role of PE synthesis in regulating metastasis and presents PCYT2 as a potential therapeutic target for CRC.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
High-dimensional analysis of NK cells in kidney transplantation uncovers subsets associated with antibody-independent graft dysfunction. 对肾移植中的 NK 细胞进行高维分析,发现与抗体依赖性移植物功能障碍相关的亚群。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.185687
Dan Fu Ruan, Miguel Fribourg, Yuko Yuki, Yeon-Hwa Park, Maureen P Martin, Haocheng Yu, Geoffrey C Kelly, Brian Lee, Ronaldo M de Real, Rachel Lee, Daniel Geanon, Seunghee Kim-Schulze, Nicholas Chun, Paolo Cravedi, Mary Carrington, Peter S Heeger, Amir Horowitz
{"title":"High-dimensional analysis of NK cells in kidney transplantation uncovers subsets associated with antibody-independent graft dysfunction.","authors":"Dan Fu Ruan, Miguel Fribourg, Yuko Yuki, Yeon-Hwa Park, Maureen P Martin, Haocheng Yu, Geoffrey C Kelly, Brian Lee, Ronaldo M de Real, Rachel Lee, Daniel Geanon, Seunghee Kim-Schulze, Nicholas Chun, Paolo Cravedi, Mary Carrington, Peter S Heeger, Amir Horowitz","doi":"10.1172/jci.insight.185687","DOIUrl":"10.1172/jci.insight.185687","url":null,"abstract":"<p><p>Natural killer (NK) cells respond to diseased and allogeneic cells through NKG2A/HLA-E or killer cell immunoglobulin-like receptor (KIR)/HLA-ABC interactions. Correlations between HLA/KIR disparities and kidney transplant pathology suggest an antibody-independent pathogenic role for NK cells in transplantation, but the mechanisms remain unclear. Using CyTOF to characterize recipient peripheral NK cell phenotypes and function, we observed diverse NK cell subsets among participants who responded heterogeneously to allo-stimulators. NKG2A+KIR+ NK cells responded more vigorously than other subsets, and this heightened response persisted after kidney transplantation despite immunosuppression. In test and validation sets from 2 clinical trials, pretransplant donor-induced release of cytotoxicity mediator Ksp37 by NKG2A+ NK cells correlated with reduced long-term allograft function. Separate analyses showed that Ksp37 gene expression in allograft biopsies lacking histological rejection correlated with death-censored graft loss. Our findings support an antibody-independent role for NK cells in transplant injury and support further testing of pretransplant, donor-reactive, NK cell-produced Ksp37 as a risk-assessing, transplantation biomarker.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Integrated analysis of rectal mucosal microbiome and transcriptome reveals a distinct microenvironment among young MSM. 直肠粘膜微生物组和转录组的综合分析揭示了年轻 MSM 的独特微环境。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.181720
Cassie G Ackerley, S Abigail Smith, Phillip M Murray, Praveen K Amancha, Vanessa E Van Doren, Gregory K Tharp, Robert A Arthur, Rama R Amara, Yi-Juan Hu, Colleen F Kelley
{"title":"Integrated analysis of rectal mucosal microbiome and transcriptome reveals a distinct microenvironment among young MSM.","authors":"Cassie G Ackerley, S Abigail Smith, Phillip M Murray, Praveen K Amancha, Vanessa E Van Doren, Gregory K Tharp, Robert A Arthur, Rama R Amara, Yi-Juan Hu, Colleen F Kelley","doi":"10.1172/jci.insight.181720","DOIUrl":"10.1172/jci.insight.181720","url":null,"abstract":"<p><p>Crosstalk between the microbiome and gut mucosa-resident immune cells plays a pivotal role in modulating immune responses to pathogens, including responses to HIV infection. However, how these interactions may differ between young men who have sex with men (YMSM) disproportionately impacted by HIV, as compared with older adult MSM (AMSM), is not well understood. A broad analysis of associations between the microbiome and rectal transcriptome revealed 10 microbial families/genera correlated with immunologic gene pathways. Specifically, the rectal transcriptome of YMSM was characterized by upregulation of T cell activation/differentiation pathways and signaling from multiple cytokine families compared with AMSM. The microbiome of YMSM was enriched with pathogenic genera, including Peptostreptococcus, shown to be positively correlated with type I IFN pathways important for antiviral immunity. These findings demonstrate that YMSM have a unique immune phenotype and rectal microenvironment and support further evaluation of biological factors that influence rectal HIV transmission.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma. SLC4A11介导氨的输入并促进肝细胞癌的癌干性。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.184826
Ameer L Elaimy, Marwa O El-Derany, Jadyn James, Zhuwen Wang, Ashley N Pearson, Erin A Holcomb, Amanda K Huber, Miguel Gijón, Hannah N Bell, Viraj R Sanghvi, Timothy L Frankel, Grace L Su, Elliot B Tapper, Andrew W Tai, Nithya Ramnath, Christopher P Centonze, Irina Dobrosotskaya, Julie A Moeller, Alex K Bryant, David A Elliott, Enid Choi, Joseph R Evans, Kyle C Cuneo, Thomas J Fitzgerald, Daniel R Wahl, Meredith A Morgan, Daniel T Chang, Max S Wicha, Theodore S Lawrence, Yatrik M Shah, Michael D Green
{"title":"SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma.","authors":"Ameer L Elaimy, Marwa O El-Derany, Jadyn James, Zhuwen Wang, Ashley N Pearson, Erin A Holcomb, Amanda K Huber, Miguel Gijón, Hannah N Bell, Viraj R Sanghvi, Timothy L Frankel, Grace L Su, Elliot B Tapper, Andrew W Tai, Nithya Ramnath, Christopher P Centonze, Irina Dobrosotskaya, Julie A Moeller, Alex K Bryant, David A Elliott, Enid Choi, Joseph R Evans, Kyle C Cuneo, Thomas J Fitzgerald, Daniel R Wahl, Meredith A Morgan, Daniel T Chang, Max S Wicha, Theodore S Lawrence, Yatrik M Shah, Michael D Green","doi":"10.1172/jci.insight.184826","DOIUrl":"10.1172/jci.insight.184826","url":null,"abstract":"<p><p>End-stage liver disease is marked by portal hypertension, systemic elevations in ammonia, and development of hepatocellular carcinoma (HCC). While these clinical consequences of cirrhosis are well described, it remains poorly understood whether hepatic insufficiency and the accompanying elevations in ammonia contribute to HCC carcinogenesis. Using preclinical models, we discovered that ammonia entered the cell through the transporter SLC4A11 and served as a nitrogen source for amino acid and nucleotide biosynthesis. Elevated ammonia promoted cancer stem cell properties in vitro and tumor initiation in vivo. Enhancing ammonia clearance reduced HCC stemness and tumor growth. In patients, elevations in serum ammonia were associated with an increased incidence of HCC. Taken together, this study forms the foundation for clinical investigations using ammonia-lowering agents as potential therapies to mitigate HCC incidence and aggressiveness.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibition of Bruton's tyrosine kinase with PD-1 blockade modulates T cell activation in solid tumors. 用 PD-1 阻断剂抑制布鲁顿酪氨酸激酶可调节实体瘤中 T 细胞的活化。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.169927
Emily Schwarz, Brooke Benner, Robert Wesolowski, Dionisia Quiroga, Logan Good, Steven H Sun, Himanshu Savardekar, Jianying Li, Kyeong Joo Jung, Megan C Duggan, Gabriella Lapurga, Jami Shaffer, Luke Scarberry, Bhavana Konda, Claire Verschraegen, Kari Kendra, Manisha Shah, Robert Rupert, Paul Monk, Hiral A Shah, Anne M Noonan, Kristin Bixel, John Hays, Lai Wei, Xueliang Pan, Gregory Behbehani, Yang Hu, Olivier Elemento, Dongjun Chung, Gang Xin, Bradley W Blaser, William E Carson
{"title":"Inhibition of Bruton's tyrosine kinase with PD-1 blockade modulates T cell activation in solid tumors.","authors":"Emily Schwarz, Brooke Benner, Robert Wesolowski, Dionisia Quiroga, Logan Good, Steven H Sun, Himanshu Savardekar, Jianying Li, Kyeong Joo Jung, Megan C Duggan, Gabriella Lapurga, Jami Shaffer, Luke Scarberry, Bhavana Konda, Claire Verschraegen, Kari Kendra, Manisha Shah, Robert Rupert, Paul Monk, Hiral A Shah, Anne M Noonan, Kristin Bixel, John Hays, Lai Wei, Xueliang Pan, Gregory Behbehani, Yang Hu, Olivier Elemento, Dongjun Chung, Gang Xin, Bradley W Blaser, William E Carson","doi":"10.1172/jci.insight.169927","DOIUrl":"https://doi.org/10.1172/jci.insight.169927","url":null,"abstract":"<p><p>BACKGROUNDInhibition of Bruton's tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The combination of ibrutinib and nivolumab was tested in patients with metastatic solid tumors.METHODSSixteen patients received ibrutinib 420 mg p.o. daily with nivolumab 240 mg i.v. on days 1 and 15 of a 28-day cycle. The effect of ibrutinib and nivolumab on MDSC, the immune profile, and cytokine levels were measured. Single-cell RNA-Seq and T cell receptor sequencing of immune cells was performed.RESULTSCommon adverse events were fatigue and anorexia. Four patients had partial responses and 4 had stable disease at 3 months (average 6.5 months, range 3.5-14.6). Median overall survival (OS) was 10.8 months. Seven days of Bruton's tyrosine kinase (BTK) inhibition significantly increased the proportion of monocytic-MDSC (M-MDSC) and significantly decreased chemokines associated with MDSC recruitment and accumulation (CCL2, CCL3, CCL4, CCL13). Single-cell RNA-Seq revealed ibrutinib-induced downregulation of genes associated with MDSC-suppressive function (TIMP1, CXCL8, VEGFA, HIF1A), reduced MDSC interactions with exhausted CD8+ T cells, and decreased TCR repertoire diversity. The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSIONIbrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT03525925.FUNDINGNIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 21","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tet2-mediated clonal hematopoiesis in non-conditioned mice accelerates age-associated cardiac dysfunction. Tet2介导的非条件小鼠克隆造血加速了年龄相关性心脏功能障碍。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.187715
Ying Wang, Soichi Sano, Yoshimitsu Yura, Zhonghe Ke, Miho Sano, Kosei Oshima, Hayato Ogawa, Keita Horitani, Kyung-Duk Min, Emiri Miura-Yura, Anupreet Kour, Megan A Evans, María A Zuriaga, Karen K Hirschi, Jose J Fuster, Eric M Pietras, Kenneth Walsh
{"title":"Tet2-mediated clonal hematopoiesis in non-conditioned mice accelerates age-associated cardiac dysfunction.","authors":"Ying Wang, Soichi Sano, Yoshimitsu Yura, Zhonghe Ke, Miho Sano, Kosei Oshima, Hayato Ogawa, Keita Horitani, Kyung-Duk Min, Emiri Miura-Yura, Anupreet Kour, Megan A Evans, María A Zuriaga, Karen K Hirschi, Jose J Fuster, Eric M Pietras, Kenneth Walsh","doi":"10.1172/jci.insight.187715","DOIUrl":"https://doi.org/10.1172/jci.insight.187715","url":null,"abstract":"","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 21","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology. 表皮角质细胞中的ERK过度激活会损害细胞间粘附力,并驱动格罗弗病的病理变化。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.182983
Cory L Simpson, Afua Tiwaa, Shivam A Zaver, Christopher J Johnson, Emily Y Chu, Paul W Harms, Johann E Gudjonsson
{"title":"ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology.","authors":"Cory L Simpson, Afua Tiwaa, Shivam A Zaver, Christopher J Johnson, Emily Y Chu, Paul W Harms, Johann E Gudjonsson","doi":"10.1172/jci.insight.182983","DOIUrl":"10.1172/jci.insight.182983","url":null,"abstract":"<p><p>Grover disease is an acquired epidermal blistering disorder in which keratinocytes lose intercellular connections. While its pathologic features are well defined, its etiology remains unclear, and there is no FDA-approved therapy. Interestingly, Grover disease was a common adverse event in clinical trials for cancer using B-RAF inhibitors, but it remained unknown how B-RAF blockade compromised skin integrity. Here, we identified ERK hyperactivation as a key driver of Grover disease pathology. We leveraged a fluorescent biosensor to confirm that the B-RAF inhibitors dabrafenib and vemurafenib paradoxically activated ERK in human keratinocytes and organotypic epidermis, disrupting cell-cell junctions and weakening epithelial integrity. Consistent with clinical data showing that concomitant MEK blockade prevents Grover disease in patients receiving B-RAF inhibitors, we found that MEK inhibition suppressed ERK and rescued cohesion of B-RAF-inhibited keratinocytes. Validating these results, we demonstrated ERK hyperactivation in patient biopsies from vemurafenib-induced Grover disease and from spontaneous Grover disease, revealing a common etiology for both. Finally, in line with our recent identification of ERK hyperactivation in Darier disease, a genetic disorder with identical pathology to Grover disease, our studies uncovered that the pathogenic mechanisms of these diseases converge on ERK signaling and support MEK inhibition as a therapeutic strategy.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The human milk oligosaccharide 3'sialyllactose reduces low-grade inflammation and atherosclerosis development in mice. 人乳寡糖 3'sialyllactose 可减少小鼠低度炎症和动脉粥样硬化的发生。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.181329
Ariane R Pessentheiner, Nathanael J Spann, Chloe A Autran, Tae Gyu Oh, Kaare V Grunddal, Joanna Kc Coker, Chelsea D Painter, Bastian Ramms, Austin Wt Chiang, Chen-Yi Wang, Jason Hsiao, Yiwen Wang, Anthony Quach, Laela M Booshehri, Alexandra Hammond, Chiara Tognaccini, Joanna Latasiewicz, Lisa Willemsen, Karsten Zengler, Menno Pj de Winther, Hal M Hoffman, Martin Philpott, Adam P Cribbs, Udo Oppermann, Nathan E Lewis, Joseph L Witztum, Ruth Yu, Annette R Atkins, Michael Downes, Ron M Evans, Christopher K Glass, Lars Bode, Philip Lsm Gordts
{"title":"The human milk oligosaccharide 3'sialyllactose reduces low-grade inflammation and atherosclerosis development in mice.","authors":"Ariane R Pessentheiner, Nathanael J Spann, Chloe A Autran, Tae Gyu Oh, Kaare V Grunddal, Joanna Kc Coker, Chelsea D Painter, Bastian Ramms, Austin Wt Chiang, Chen-Yi Wang, Jason Hsiao, Yiwen Wang, Anthony Quach, Laela M Booshehri, Alexandra Hammond, Chiara Tognaccini, Joanna Latasiewicz, Lisa Willemsen, Karsten Zengler, Menno Pj de Winther, Hal M Hoffman, Martin Philpott, Adam P Cribbs, Udo Oppermann, Nathan E Lewis, Joseph L Witztum, Ruth Yu, Annette R Atkins, Michael Downes, Ron M Evans, Christopher K Glass, Lars Bode, Philip Lsm Gordts","doi":"10.1172/jci.insight.181329","DOIUrl":"10.1172/jci.insight.181329","url":null,"abstract":"<p><p>Macrophages contribute to the induction and resolution of inflammation and play a central role in chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3'sialyllactose (3'SL) as a natural inhibitor of TLR4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3'SL attenuates mRNA levels of a selected set of inflammatory genes and promotes the activity of liver X receptor (LXR) and sterol regulatory element binding protein-1 (SREBP1). These acute antiinflammatory effects of 3'SL were associated with reduced histone H3K27 acetylation at a subset of LPS-inducible enhancers distinguished by preferential enrichment for CCCTC-binding factor (CTCF), IFN regulatory factor 2 (IRF2), B cell lymphoma 6 (BCL6), and other transcription factor recognition motifs. In a murine atherosclerosis model, both s.c. and oral administration of 3'SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3'SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The RNA receptor RIG-I binding synthetic oligodeoxynucleotide promotes pneumonia survival. RNA 受体 RIG-I 结合合成寡聚脱氧核苷酸可促进肺炎存活。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.180584
Yongxing Wang, Vikram V Kulkarni, Jezreel PantaleónGarcía, Michael K Longmire, Mathilde Lethier, Stephen Cusack, Scott E Evans
{"title":"The RNA receptor RIG-I binding synthetic oligodeoxynucleotide promotes pneumonia survival.","authors":"Yongxing Wang, Vikram V Kulkarni, Jezreel PantaleónGarcía, Michael K Longmire, Mathilde Lethier, Stephen Cusack, Scott E Evans","doi":"10.1172/jci.insight.180584","DOIUrl":"10.1172/jci.insight.180584","url":null,"abstract":"<p><p>Pneumonia is a worldwide threat to public health, demanding novel preventative and therapeutic strategies. The lung epithelium is a critical environmental interface that functions as a physical barrier to pathogen invasion while also actively sensing and responding to pathogens. We have reported that stimulating lung epithelial cells with a combination therapeutic consisting of a diacylated lipopeptide and a synthetic CpG oligodeoxynucleotide (ODN) induces synergistic pneumonia protection against a wide range of pathogens. We report here that mice deficient in TLR9, the previously described receptor for ODN, still displayed partial ODN-induced protection. This prompted us to seek an alternate ODN receptor, and we discovered by mass spectroscopy that the RNA sensor RIG-I could also bind DNA-like ODN. ODN binding by RIG-I resulted in MAVS-dependent pneumonia-protective signaling events. While RIG-I is essential to native defenses against viral infections, we report that therapeutic RIG-I activation with ODN promoted pathogen killing and host survival following both viral and bacterial challenges. These data indicate that maximal ODN-induced pneumonia protection requires activation of both the TLR9/MyD88 and RIG-I/MAVS signaling pathways. These findings not only identify what we believe to be a novel pattern recognition receptor for DNA-like molecules, but reveal a potential therapeutic strategy to protect susceptible individuals against lethal pneumonias during periods of peak vulnerability.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
相关产品
×
本文献相关产品
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信