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C-terminal FGF-23 production coupling with aldosterone via FAM20C and predicting cardiovascular events in primary aldosteronism.
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-24 DOI: 10.1172/jci.insight.166461
Vin-Cent Wu, Kang-Yung Peng, Tsu-I Chen, Chiao-Yin Sun, Hung-Wei Liao, Chieh-Kai Chan, Yen-Hung Lin, Hung-Hsiang Liou, Jeff S Chueh

This study examined the involvement of fibroblast growth factor-23 (FGF-23) in primary aldosteronism (PA), a condition characterized by elevated aldosterone levels and hypertension. We recruited patients with unilateral PA (uPA) and observed increased levels of C-terminal FGF-23 (cFGF-23) and C-terminal to intact FGF-23 (iFGF-23) in patients with uPA compared with essential hypertension control participants. Elevated preoperative cFGF-23 levels were associated with adverse outcomes, including mortality and cardiovascular or kidney events. Plasma cFGF-23 levels demonstrated a nonlinear rise with aldosterone, but iFGF-23 levels were not correlated with plasma aldosterone concentration. Higher cFGF-23 levels independently predicted hypertension remission after adrenalectomy for patients with uPA. Patients with uPA, who exhibited elevated cFGF-23 levels, had decreased levels after adrenalectomy. In cell cultures, aldosterone enhanced cleavage of iFGF-23, leading to increased levels of cFGF-23 fragments, an effect mitigated by silencing of family with sequence similarity 20, member C (FAM20C). However, the enhancement of cFGF-23 levels remained unaffected by the furin inhibitor. The study suggests that aldosterone influences FGF-23 phosphorylation by interacting with FAM20C, with docking experiments indicating aldosterone's binding to FAM20C. This work highlights that patients with uPA with elevated cFGF-23 levels are associated with cardiovascular risks, and adrenalectomy reduces cFGF-23. Aldosterone likely promotes cFGF-23 production through FAM20C-mediated phosphorylation of iFGF-23.

{"title":"C-terminal FGF-23 production coupling with aldosterone via FAM20C and predicting cardiovascular events in primary aldosteronism.","authors":"Vin-Cent Wu, Kang-Yung Peng, Tsu-I Chen, Chiao-Yin Sun, Hung-Wei Liao, Chieh-Kai Chan, Yen-Hung Lin, Hung-Hsiang Liou, Jeff S Chueh","doi":"10.1172/jci.insight.166461","DOIUrl":"https://doi.org/10.1172/jci.insight.166461","url":null,"abstract":"<p><p>This study examined the involvement of fibroblast growth factor-23 (FGF-23) in primary aldosteronism (PA), a condition characterized by elevated aldosterone levels and hypertension. We recruited patients with unilateral PA (uPA) and observed increased levels of C-terminal FGF-23 (cFGF-23) and C-terminal to intact FGF-23 (iFGF-23) in patients with uPA compared with essential hypertension control participants. Elevated preoperative cFGF-23 levels were associated with adverse outcomes, including mortality and cardiovascular or kidney events. Plasma cFGF-23 levels demonstrated a nonlinear rise with aldosterone, but iFGF-23 levels were not correlated with plasma aldosterone concentration. Higher cFGF-23 levels independently predicted hypertension remission after adrenalectomy for patients with uPA. Patients with uPA, who exhibited elevated cFGF-23 levels, had decreased levels after adrenalectomy. In cell cultures, aldosterone enhanced cleavage of iFGF-23, leading to increased levels of cFGF-23 fragments, an effect mitigated by silencing of family with sequence similarity 20, member C (FAM20C). However, the enhancement of cFGF-23 levels remained unaffected by the furin inhibitor. The study suggests that aldosterone influences FGF-23 phosphorylation by interacting with FAM20C, with docking experiments indicating aldosterone's binding to FAM20C. This work highlights that patients with uPA with elevated cFGF-23 levels are associated with cardiovascular risks, and adrenalectomy reduces cFGF-23. Aldosterone likely promotes cFGF-23 production through FAM20C-mediated phosphorylation of iFGF-23.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 4","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483185","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
SPP1hi macrophages, NKG7 T cells, CCL5hi fibroblasts, and IgM plasma cells are dominant features of necrobiosis.
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-24 DOI: 10.1172/jci.insight.178766
Stephanie T Le, Alina I Marusina, Alexander A Merleev, Amanda Kirane, Olga Kruglinskaya, Andrey Kunitsyn, Nikolay Yu Kuzminykh, Xianying Xing, Sophie Y Li, William Liakos, J Michelle Kahlenberg, Andrea Gompers, Lauren Downing, Sahiti Marella, Allison C Billi, Paul W Harms, Lam C Tsoi, Marie-Charlotte Brüggen, Iannis E Adamopoulos, Johann E Gudjonsson, Emanual Maverakis

Necrobiosis is a histologic term used to describe abnormal deposits of "degenerating" collagen within the skin. It can be found as an incidental finding in various granulomatous conditions, but is a hallmark of necrobiosis lipoidica (NL) and necrobiotic xanthogranuloma (NXG). There is limited prior research on necrobiosis. Here, we employed single-cell analysis of lesional and nonlesional skin to study the pathophysiology of necrobiosis. Our findings demonstrate that necrobiotic lesional skin is characterized by SPP1hi macrophages expressing MARCO; NKG7-expressing effector CD8+ T cells coexpressing CCL5, IFNG, GZMs, and PRF1; CCL5hi fibroblasts coexpressing CXCL9, diverse collagens (e.g., COL4A4, COL11A1, COL8A1), and TIMP1; and IGHM-expressing plasma cells. Integrative analysis of signaling ligands and receptor expression identified strong cell-cell communication between NKG7+ T cells, CCL5hi fibroblasts, and SPP1-expressing macrophages. In contrast, these cell populations were not dominant features of systemic sclerosis, another collagen deposition disease. Furthermore, although SPP1-expressing macrophages were detectable in sarcoidosis, IFNG-expressing T cells were a more defining feature of sarcoidosis compared with NL and NXG. From these findings, we speculate that necrobiosis results from the deposition of diverse collagens and ECM proteins through a process driven by CCL5-expressing fibroblasts and SPP1-expressing macrophages.

{"title":"SPP1hi macrophages, NKG7 T cells, CCL5hi fibroblasts, and IgM plasma cells are dominant features of necrobiosis.","authors":"Stephanie T Le, Alina I Marusina, Alexander A Merleev, Amanda Kirane, Olga Kruglinskaya, Andrey Kunitsyn, Nikolay Yu Kuzminykh, Xianying Xing, Sophie Y Li, William Liakos, J Michelle Kahlenberg, Andrea Gompers, Lauren Downing, Sahiti Marella, Allison C Billi, Paul W Harms, Lam C Tsoi, Marie-Charlotte Brüggen, Iannis E Adamopoulos, Johann E Gudjonsson, Emanual Maverakis","doi":"10.1172/jci.insight.178766","DOIUrl":"https://doi.org/10.1172/jci.insight.178766","url":null,"abstract":"<p><p>Necrobiosis is a histologic term used to describe abnormal deposits of \"degenerating\" collagen within the skin. It can be found as an incidental finding in various granulomatous conditions, but is a hallmark of necrobiosis lipoidica (NL) and necrobiotic xanthogranuloma (NXG). There is limited prior research on necrobiosis. Here, we employed single-cell analysis of lesional and nonlesional skin to study the pathophysiology of necrobiosis. Our findings demonstrate that necrobiotic lesional skin is characterized by SPP1hi macrophages expressing MARCO; NKG7-expressing effector CD8+ T cells coexpressing CCL5, IFNG, GZMs, and PRF1; CCL5hi fibroblasts coexpressing CXCL9, diverse collagens (e.g., COL4A4, COL11A1, COL8A1), and TIMP1; and IGHM-expressing plasma cells. Integrative analysis of signaling ligands and receptor expression identified strong cell-cell communication between NKG7+ T cells, CCL5hi fibroblasts, and SPP1-expressing macrophages. In contrast, these cell populations were not dominant features of systemic sclerosis, another collagen deposition disease. Furthermore, although SPP1-expressing macrophages were detectable in sarcoidosis, IFNG-expressing T cells were a more defining feature of sarcoidosis compared with NL and NXG. From these findings, we speculate that necrobiosis results from the deposition of diverse collagens and ECM proteins through a process driven by CCL5-expressing fibroblasts and SPP1-expressing macrophages.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 4","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483253","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
Frequency of dengue virus-specific T cells is related to infection outcome in endemic settings.
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-24 DOI: 10.1172/jci.insight.179771
Rosa Isela Gálvez, Amparo Martínez-Pérez, E Alexandar Escarrega, Tulika Singh, José Victor Zambrana, Ángel Balmaseda, Eva Harris, Daniela Weiskopf

Dengue is widespread in tropical and subtropical regions globally and imposes a considerable disease burden. Annually, dengue virus (DENV) causes up to 400 million infections, of which approximately 25% present with clinical manifestations ranging from mild to fatal. Despite its significance as a growing public health concern, developing effective DENV vaccines has been challenging. One reason is the lack of comprehensive understanding of the influence exerted by prior DENV infections and immune responses with cross-reactive properties. To investigate this, we collected samples from a pediatric cohort study in dengue-endemic Managua, Nicaragua. We characterized T cell responses in 71 healthy children who had previously experienced 1 or more natural DENV infections and who, within 1 year after sample collection, had a subsequent DENV infection that was either symptomatic or inapparent. Our study investigated the effect of preexisting DENV-specific T cell responses on clinical outcomes of subsequent DENV infection. We assessed DENV-specific T cell responses using an activation-induced marker assay. Children with only 1 prior DENV infection displayed heterogeneous DENV-specific CD4+ and CD8+ T cell frequencies. In contrast, children with 2 or more prior DENV infections showed significantly higher DENV-specific CD4+ and CD8+ T cell frequencies associated with inapparent rather than symptomatic outcomes in subsequent infection. These findings demonstrate the protective role of DENV-specific T cells against symptomatic DENV infection and advance efforts to identify protective immune correlates against dengue.

{"title":"Frequency of dengue virus-specific T cells is related to infection outcome in endemic settings.","authors":"Rosa Isela Gálvez, Amparo Martínez-Pérez, E Alexandar Escarrega, Tulika Singh, José Victor Zambrana, Ángel Balmaseda, Eva Harris, Daniela Weiskopf","doi":"10.1172/jci.insight.179771","DOIUrl":"10.1172/jci.insight.179771","url":null,"abstract":"<p><p>Dengue is widespread in tropical and subtropical regions globally and imposes a considerable disease burden. Annually, dengue virus (DENV) causes up to 400 million infections, of which approximately 25% present with clinical manifestations ranging from mild to fatal. Despite its significance as a growing public health concern, developing effective DENV vaccines has been challenging. One reason is the lack of comprehensive understanding of the influence exerted by prior DENV infections and immune responses with cross-reactive properties. To investigate this, we collected samples from a pediatric cohort study in dengue-endemic Managua, Nicaragua. We characterized T cell responses in 71 healthy children who had previously experienced 1 or more natural DENV infections and who, within 1 year after sample collection, had a subsequent DENV infection that was either symptomatic or inapparent. Our study investigated the effect of preexisting DENV-specific T cell responses on clinical outcomes of subsequent DENV infection. We assessed DENV-specific T cell responses using an activation-induced marker assay. Children with only 1 prior DENV infection displayed heterogeneous DENV-specific CD4+ and CD8+ T cell frequencies. In contrast, children with 2 or more prior DENV infections showed significantly higher DENV-specific CD4+ and CD8+ T cell frequencies associated with inapparent rather than symptomatic outcomes in subsequent infection. These findings demonstrate the protective role of DENV-specific T cells against symptomatic DENV infection and advance efforts to identify protective immune correlates against dengue.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 4","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483205","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
Digenic impairments of haploinsufficient genes in patients with craniosynostosis.
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-24 DOI: 10.1172/jci.insight.176985
Jung Woo Yu, Jihoon G Yoon, Chaerim Han, Shin Hye Noh, Dong Min Shin, Yu-Mi Yang, Yong Oock Kim, Kyu-Won Shim, Min Goo Lee

Craniosynostosis (CRS) is characterized by the development of abnormal cranial suture ossification and premature fusion. Despite the identification of several associated genetic disorders, the genetic determinants of CRS remain poorly understood. In this study, we conducted integrative analyses on 225 exomes, comprising 121 CRS probands and 104 parental exomes (52 trios). These analyses encompassed de novo and pathogenic variants, and digenic combinations within haploinsufficient genes harboring rare variants. Our analysis unveils a shared molecular network between genes associated with CRS and those linked to skeletal and neurodevelopmental disorders, with a notable enrichment of deleterious variants within haploinsufficient genes. Additionally, we identified a unique digenic pair (IL6ST and TRPS1) within haploinsufficient genes that was present in 2 patients with nonsyndromic CRS but absent in parents or 1,048 population controls. In vitro experiments provided evidence that the identified missense variants were hypomorphs, and accelerated bone mineralization could result from the additive effects of diminished IL6ST and TRPS1 activities in osteoblasts. Overall, our study underscores the important role of rare variations in haploinsufficient genes and suggests that in a subset of undiagnosed patients, the CRS phenotype may arise from multiple genetic variations.

{"title":"Digenic impairments of haploinsufficient genes in patients with craniosynostosis.","authors":"Jung Woo Yu, Jihoon G Yoon, Chaerim Han, Shin Hye Noh, Dong Min Shin, Yu-Mi Yang, Yong Oock Kim, Kyu-Won Shim, Min Goo Lee","doi":"10.1172/jci.insight.176985","DOIUrl":"https://doi.org/10.1172/jci.insight.176985","url":null,"abstract":"<p><p>Craniosynostosis (CRS) is characterized by the development of abnormal cranial suture ossification and premature fusion. Despite the identification of several associated genetic disorders, the genetic determinants of CRS remain poorly understood. In this study, we conducted integrative analyses on 225 exomes, comprising 121 CRS probands and 104 parental exomes (52 trios). These analyses encompassed de novo and pathogenic variants, and digenic combinations within haploinsufficient genes harboring rare variants. Our analysis unveils a shared molecular network between genes associated with CRS and those linked to skeletal and neurodevelopmental disorders, with a notable enrichment of deleterious variants within haploinsufficient genes. Additionally, we identified a unique digenic pair (IL6ST and TRPS1) within haploinsufficient genes that was present in 2 patients with nonsyndromic CRS but absent in parents or 1,048 population controls. In vitro experiments provided evidence that the identified missense variants were hypomorphs, and accelerated bone mineralization could result from the additive effects of diminished IL6ST and TRPS1 activities in osteoblasts. Overall, our study underscores the important role of rare variations in haploinsufficient genes and suggests that in a subset of undiagnosed patients, the CRS phenotype may arise from multiple genetic variations.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 4","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483189","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
Virologic effects of broadly neutralizing antibodies VRC01LS and VRC07-523LS on chronic HIV-1 infection.
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-24 DOI: 10.1172/jci.insight.181496
Myra Happe, Rebecca M Lynch, Carl J Fichtenbaum, Sonya L Heath, Susan L Koletar, Raphael J Landovitz, Rachel M Presti, Jorge L Santana-Bagur, Randall L Tressler, LaSonji A Holman, Laura Novik, Jhoanna C Roa, Ro Shauna Rothwell, Larisa Strom, Jing Wang, Zonghui Hu, Michelle Conan-Cibotti, Anjali M Bhatnagar, Bridget Dwyer, Sung Hee Ko, Frida Belinky, Aryan M Namboodiri, Janardan P Pandey, Robin Carroll, Manjula Basappa, Leonid Serebryannyy, Sandeep R Narpala, Bob C Lin, Adrian B McDermott, Eli A Boritz, Edmund V Capparelli, Emily E Coates, Richard A Koup, Julie E Ledgerwood, John R Mascola, Grace L Chen, Pablo Tebas

BACKGROUNDHIV-1-specific broadly neutralizing monoclonal antibodies (bNAbs) have emerged as promising interventions with the potential to effectively treat and prevent HIV-1 infections. We conducted a phase I clinical trial evaluating the potent CD4-binding site-specific (CD4bs-specific) bNAbs VRC01LS and VRC07-523LS in people with HIV-1 (PWH) not receiving antiretroviral therapy (ART).METHODSParticipants received a single intravenous 40 mg/kg dose of either VRC01LS (n = 7) or VRC07-523LS (n = 9) and did not initiate ART for a minimum of 14 days. The primary study objective was to evaluate safety and tolerability; the secondary study objectives were to evaluate pharmacokinetics (PK) and the impact of administered bNAbs on viral loads (VL) and CD4+ T cell counts in the absence of ART.RESULTSThis trial enrolled 16 PWH aged 20 to 57 years. Both bNAbs were safe and well tolerated. Mild local reactogenicity was only reported in participants who received VRC07-523LS, while both bNAbs were associated with mild systemic symptoms. Maximum serum concentrations (Cmax) following VRC01LS or VRC07-523LS were 1,566 ± 316 and 1,295 ± 376 μg/mL, respectively. VRC07-523LS administration significantly decreased VL in 8 out of 9 participants, with an average decline of 1.7 ± 0.8 log10 copies/mL within 14 days after administration. In contrast, VRC01LS administration resulted in a smaller average decline (0.8 ± 0.8 log10 copies/mL), and 3 out of 7 participants showedno change in VL. Postinfusion maximum decline in VL correlated with post hoc baseline in vitro viral susceptibility results for both bNAbs.CONCLUSIONThe results of this trial support inclusion of potent CD4bs-specific bNAbs, such as VRC07-523LS, into next-generation treatment regimens for HIV-1.TRIAL REGISTRATIONClinicalTrials.gov NCT02840474.FUNDINGNational Institute of Allergy and Infectious Diseases (NIAID)/NIH (grants UM1 AI068634, UM1 AI068636, UM1 AI106701, UM1AI069424, UM1AI069501, UM1AI69415, UM1AI069534, UM1AI69494); the Intramural Research Program of the NIAID/NIH; National Center for Advancing Translational Sciences/NIH (grants UM1TR004548, UL1TR001881, and UL1TR001878); and the National Cancer Institute/NIH (contract 75N91019D00024).

{"title":"Virologic effects of broadly neutralizing antibodies VRC01LS and VRC07-523LS on chronic HIV-1 infection.","authors":"Myra Happe, Rebecca M Lynch, Carl J Fichtenbaum, Sonya L Heath, Susan L Koletar, Raphael J Landovitz, Rachel M Presti, Jorge L Santana-Bagur, Randall L Tressler, LaSonji A Holman, Laura Novik, Jhoanna C Roa, Ro Shauna Rothwell, Larisa Strom, Jing Wang, Zonghui Hu, Michelle Conan-Cibotti, Anjali M Bhatnagar, Bridget Dwyer, Sung Hee Ko, Frida Belinky, Aryan M Namboodiri, Janardan P Pandey, Robin Carroll, Manjula Basappa, Leonid Serebryannyy, Sandeep R Narpala, Bob C Lin, Adrian B McDermott, Eli A Boritz, Edmund V Capparelli, Emily E Coates, Richard A Koup, Julie E Ledgerwood, John R Mascola, Grace L Chen, Pablo Tebas","doi":"10.1172/jci.insight.181496","DOIUrl":"https://doi.org/10.1172/jci.insight.181496","url":null,"abstract":"<p><p>BACKGROUNDHIV-1-specific broadly neutralizing monoclonal antibodies (bNAbs) have emerged as promising interventions with the potential to effectively treat and prevent HIV-1 infections. We conducted a phase I clinical trial evaluating the potent CD4-binding site-specific (CD4bs-specific) bNAbs VRC01LS and VRC07-523LS in people with HIV-1 (PWH) not receiving antiretroviral therapy (ART).METHODSParticipants received a single intravenous 40 mg/kg dose of either VRC01LS (n = 7) or VRC07-523LS (n = 9) and did not initiate ART for a minimum of 14 days. The primary study objective was to evaluate safety and tolerability; the secondary study objectives were to evaluate pharmacokinetics (PK) and the impact of administered bNAbs on viral loads (VL) and CD4+ T cell counts in the absence of ART.RESULTSThis trial enrolled 16 PWH aged 20 to 57 years. Both bNAbs were safe and well tolerated. Mild local reactogenicity was only reported in participants who received VRC07-523LS, while both bNAbs were associated with mild systemic symptoms. Maximum serum concentrations (Cmax) following VRC01LS or VRC07-523LS were 1,566 ± 316 and 1,295 ± 376 μg/mL, respectively. VRC07-523LS administration significantly decreased VL in 8 out of 9 participants, with an average decline of 1.7 ± 0.8 log10 copies/mL within 14 days after administration. In contrast, VRC01LS administration resulted in a smaller average decline (0.8 ± 0.8 log10 copies/mL), and 3 out of 7 participants showedno change in VL. Postinfusion maximum decline in VL correlated with post hoc baseline in vitro viral susceptibility results for both bNAbs.CONCLUSIONThe results of this trial support inclusion of potent CD4bs-specific bNAbs, such as VRC07-523LS, into next-generation treatment regimens for HIV-1.TRIAL REGISTRATIONClinicalTrials.gov NCT02840474.FUNDINGNational Institute of Allergy and Infectious Diseases (NIAID)/NIH (grants UM1 AI068634, UM1 AI068636, UM1 AI106701, UM1AI069424, UM1AI069501, UM1AI69415, UM1AI069534, UM1AI69494); the Intramural Research Program of the NIAID/NIH; National Center for Advancing Translational Sciences/NIH (grants UM1TR004548, UL1TR001881, and UL1TR001878); and the National Cancer Institute/NIH (contract 75N91019D00024).</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 4","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483254","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
CD103+ dendritic cell - fibroblast crosstalk via TLR9, TDO2, and AHR signaling drives lung fibrogenesis.
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-18 DOI: 10.1172/jci.insight.177072
Hannah Carter, Rita Medina Costa, Taylor S Adams, Talon M Gilchrist, Claire E Emch, Monica Bame, Justin M Oldham, Steven K Huang, Angela L Linderholm, Imre Noth, Naftali Kaminski, Bethany B Moore, Stephen J Gurczynski

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients succumb to the disease within 2 to 5 years. The molecular pathogenesis of IPF regarding the immunologic changes that occur is poorly understood. We characterize a role for non-canonical aryl-hydrocarbon receptor signaling (ncAHR) in dendritic cells (DCs) that leads to production of IL-6 and increased IL-17+ cells, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2 which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing floxed AHR exon-2 deletion mice (AHRΔex2) with mice harboring a CD11c-Cre. Bleomycin (blm) was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex-vivo with relevant TLR agonists and AHR modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis, however, AHRΔex2 mice treated with blm developed more fibrosis and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2 and fibrotic fibroblasts activated IL-6 production in CD103+ DCs. Study of human samples corroborates the relevance of these findings in IPF patients. We also, for the first time, identify that AHR exon-2 floxed mice retain capacity for ncAHR signaling.

{"title":"CD103+ dendritic cell - fibroblast crosstalk via TLR9, TDO2, and AHR signaling drives lung fibrogenesis.","authors":"Hannah Carter, Rita Medina Costa, Taylor S Adams, Talon M Gilchrist, Claire E Emch, Monica Bame, Justin M Oldham, Steven K Huang, Angela L Linderholm, Imre Noth, Naftali Kaminski, Bethany B Moore, Stephen J Gurczynski","doi":"10.1172/jci.insight.177072","DOIUrl":"10.1172/jci.insight.177072","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients succumb to the disease within 2 to 5 years. The molecular pathogenesis of IPF regarding the immunologic changes that occur is poorly understood. We characterize a role for non-canonical aryl-hydrocarbon receptor signaling (ncAHR) in dendritic cells (DCs) that leads to production of IL-6 and increased IL-17+ cells, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2 which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing floxed AHR exon-2 deletion mice (AHRΔex2) with mice harboring a CD11c-Cre. Bleomycin (blm) was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex-vivo with relevant TLR agonists and AHR modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis, however, AHRΔex2 mice treated with blm developed more fibrosis and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2 and fibrotic fibroblasts activated IL-6 production in CD103+ DCs. Study of human samples corroborates the relevance of these findings in IPF patients. We also, for the first time, identify that AHR exon-2 floxed mice retain capacity for ncAHR signaling.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448815","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
Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer.
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-18 DOI: 10.1172/jci.insight.185946
Mikayla Borthwick Bowen, Brenda Melendez, Qian Zhang, Diana Moreno, Leah Peralta, Wai-Kin Chan, Collene Jeter, Lin Tan, M Anna Zal, Philip L Lorenzi, Kenneth Dunner, Richard K Yang, Russell R Broaddus, Joseph Celestino, Nisha Gokul, Elizabeth Whitley, Deena M Scoville, Tae Hoon Kim, Jae-Wook Jeong, Rosemarie Schmandt, Karen Lu, Hyun-Eui Kim, Melinda S Yates

Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, mechanisms driving LS-associated EC remain unclear. We investigated MSH2 loss in EC pathogenesis using a mouse model (PR-Cre Msh2LoxP/LoxP, abbreviated Msh2KO), primary cell lines, human tissues, and human EC cells with isogenic MSH2 knockdown. By eight months, 58% of Msh2KO mice developed endometrial atypical hyperplasia (AH), a precancerous lesion. At 12-16 months, 47% of Msh2KO mice exhibited either AH or ECs with histologic similarities to human LS-ECs. Transcriptomic profiling of EC from Msh2KO mice revealed mitochondrial dysfunction-related pathway alterations. Subsequent studies in vitro and in vivo revealed mitochondrial dysfunction based upon two mechanisms: mitochondrial content reduction and structural disruptions in retained mitochondria. Human LS-ECs also exhibited mitochondrial content reduction compared to non-LS-ECs. Functional studies demonstrated metabolic reprogramming of MSH2-deficient EC cells, including reduced oxidative phosphorylation and increased susceptibility to glycolysis suppression. These findings identified mitochondrial dysfunction and metabolic disruption as consequences of MSH2 deficiency in EC. Mitochondrial and metabolic aberrations should be evaluated as biomarkers for endometrial carcinogenesis or risk stratification and represent potential targets for cancer interception in women with LS.

{"title":"Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer.","authors":"Mikayla Borthwick Bowen, Brenda Melendez, Qian Zhang, Diana Moreno, Leah Peralta, Wai-Kin Chan, Collene Jeter, Lin Tan, M Anna Zal, Philip L Lorenzi, Kenneth Dunner, Richard K Yang, Russell R Broaddus, Joseph Celestino, Nisha Gokul, Elizabeth Whitley, Deena M Scoville, Tae Hoon Kim, Jae-Wook Jeong, Rosemarie Schmandt, Karen Lu, Hyun-Eui Kim, Melinda S Yates","doi":"10.1172/jci.insight.185946","DOIUrl":"10.1172/jci.insight.185946","url":null,"abstract":"<p><p>Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, mechanisms driving LS-associated EC remain unclear. We investigated MSH2 loss in EC pathogenesis using a mouse model (PR-Cre Msh2LoxP/LoxP, abbreviated Msh2KO), primary cell lines, human tissues, and human EC cells with isogenic MSH2 knockdown. By eight months, 58% of Msh2KO mice developed endometrial atypical hyperplasia (AH), a precancerous lesion. At 12-16 months, 47% of Msh2KO mice exhibited either AH or ECs with histologic similarities to human LS-ECs. Transcriptomic profiling of EC from Msh2KO mice revealed mitochondrial dysfunction-related pathway alterations. Subsequent studies in vitro and in vivo revealed mitochondrial dysfunction based upon two mechanisms: mitochondrial content reduction and structural disruptions in retained mitochondria. Human LS-ECs also exhibited mitochondrial content reduction compared to non-LS-ECs. Functional studies demonstrated metabolic reprogramming of MSH2-deficient EC cells, including reduced oxidative phosphorylation and increased susceptibility to glycolysis suppression. These findings identified mitochondrial dysfunction and metabolic disruption as consequences of MSH2 deficiency in EC. Mitochondrial and metabolic aberrations should be evaluated as biomarkers for endometrial carcinogenesis or risk stratification and represent potential targets for cancer interception in women with LS.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448842","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
Complement activation at the interface between adipocytes and cancer cells drives tumor progression.
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-18 DOI: 10.1172/jci.insight.184935
Andres Valdivia, Ana Isac, Horacio Cardenas, Guangyuan Zhao, Yaqi Zhang, Hao Huang, Jian-Jun Wei, Mauricio Cuello-Fredes, Sumie Kato, Fernán Gómez-Valenzuela, Francoise A Gourronc, Aloysius J Klingelhutz, Daniela Matei

The omentum is the primary site of metastasis for ovarian cancer (OC). Interactions between cancer cells and adipocytes drive an invasive and pro-metastatic phenotype. Here we studied cancer cell-adipocyte crosstalk by using a direct co-culture model with immortalized human visceral pre-adipocytes (VNPAD) and OC cells. We demonstrate increased proliferation, invasiveness, and resistance to cisplatin of co-cultured compared to mono-cultured OC cells. RNA-sequencing of OC cells from co-culture vs. mono-culture revealed significant transcriptomic changes, identifying over 200 differentially expressed genes (DEGs) common to OVCAR5 and OVCAR8 cell lines. Enriched pathways included PI3K/AKT and Complement activation. Lipid transfer into OC cells from adipocytes induced upregulation of complement C3 and C5 proteins. Inhibiting C3 or C5 reversed the invasive phenotype and C3 knockdown reduced tumor progression in-vivo. Increased C3 expression was observed in omental implants compared to primary ovarian tumors and C3 secretion was higher in OC ascites from high BMI vs. low BMI patients. C3 upregulation in OC cells involved activation of ATF4-mediated integrated stress response (ISR). Overall, adipocyte-cancer cell interactions promote invasiveness and tumorigenesis via lipid transfer, activating ISR, and upregulating complement proteins C3 and C5.

{"title":"Complement activation at the interface between adipocytes and cancer cells drives tumor progression.","authors":"Andres Valdivia, Ana Isac, Horacio Cardenas, Guangyuan Zhao, Yaqi Zhang, Hao Huang, Jian-Jun Wei, Mauricio Cuello-Fredes, Sumie Kato, Fernán Gómez-Valenzuela, Francoise A Gourronc, Aloysius J Klingelhutz, Daniela Matei","doi":"10.1172/jci.insight.184935","DOIUrl":"https://doi.org/10.1172/jci.insight.184935","url":null,"abstract":"<p><p>The omentum is the primary site of metastasis for ovarian cancer (OC). Interactions between cancer cells and adipocytes drive an invasive and pro-metastatic phenotype. Here we studied cancer cell-adipocyte crosstalk by using a direct co-culture model with immortalized human visceral pre-adipocytes (VNPAD) and OC cells. We demonstrate increased proliferation, invasiveness, and resistance to cisplatin of co-cultured compared to mono-cultured OC cells. RNA-sequencing of OC cells from co-culture vs. mono-culture revealed significant transcriptomic changes, identifying over 200 differentially expressed genes (DEGs) common to OVCAR5 and OVCAR8 cell lines. Enriched pathways included PI3K/AKT and Complement activation. Lipid transfer into OC cells from adipocytes induced upregulation of complement C3 and C5 proteins. Inhibiting C3 or C5 reversed the invasive phenotype and C3 knockdown reduced tumor progression in-vivo. Increased C3 expression was observed in omental implants compared to primary ovarian tumors and C3 secretion was higher in OC ascites from high BMI vs. low BMI patients. C3 upregulation in OC cells involved activation of ATF4-mediated integrated stress response (ISR). Overall, adipocyte-cancer cell interactions promote invasiveness and tumorigenesis via lipid transfer, activating ISR, and upregulating complement proteins C3 and C5.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448821","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 histone methyltransferase EZH2 for immune-interception of colorectal cancer in Lynch syndrome.
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-13 DOI: 10.1172/jci.insight.177545
Charles M Bowen, Fahriye Duzagac, Abel Martel-Martel, Laura Reyes-Uribe, Mahira Zaheer, Jacklyn Thompson, Nan Deng, Ria Sinha, Soham Mazumdar, Melissa W Taggart, Abhinav K Jain, Winfried Edelmann, Krishna M Sinha, Eduardo Vilar

Colorectal pre-cancers in Lynch Syndrome (LS) exhibit a distinct immune profile, presenting unique opportunities for developing immune-interception strategies to prevent carcinogenesis. Epigenetic modulation by EZH2 of immune-related genes is implicated in the carcinogenesis of different cancer types including colorectal. This study utilizes a mouse model of LS and ex vivo colonic organoids to assess the effects of the EZH2 inhibitor GSK503 on immune regulatory pathways, tumorigenesis, and epigenetic reprogramming. Our findings revealed that GSK503 significantly increased CD4+ and CD8+ T cells in both splenocytes and colonic mucosa of treated mice compared to controls. Additionally, a preventive dose of GSK503 over 9 weeks notably reduced adenoma multiplicity, demonstrating its efficacy as a preventive modality. Single-cell RNA sequencing and molecular analyses showed activation of immune and apoptotic markers, along with a reduction in H3K27 methylation levels in colonic crypts. ChIP sequencing further revealed decreased levels of H3K27me3 and H3K4me1, while levels of the active enhancer marks H3K4me3 and H3K27Ac increased in treated mice. Collectively, these findings indicate that EZH2 inhibition enhances immune responses through epigenetic reprogramming in the genome of LS mice, establishing a promising framework for the clinical development of EZH2 inhibitors as a cancer prevention strategy for LS carriers.

{"title":"Inhibition of histone methyltransferase EZH2 for immune-interception of colorectal cancer in Lynch syndrome.","authors":"Charles M Bowen, Fahriye Duzagac, Abel Martel-Martel, Laura Reyes-Uribe, Mahira Zaheer, Jacklyn Thompson, Nan Deng, Ria Sinha, Soham Mazumdar, Melissa W Taggart, Abhinav K Jain, Winfried Edelmann, Krishna M Sinha, Eduardo Vilar","doi":"10.1172/jci.insight.177545","DOIUrl":"https://doi.org/10.1172/jci.insight.177545","url":null,"abstract":"<p><p>Colorectal pre-cancers in Lynch Syndrome (LS) exhibit a distinct immune profile, presenting unique opportunities for developing immune-interception strategies to prevent carcinogenesis. Epigenetic modulation by EZH2 of immune-related genes is implicated in the carcinogenesis of different cancer types including colorectal. This study utilizes a mouse model of LS and ex vivo colonic organoids to assess the effects of the EZH2 inhibitor GSK503 on immune regulatory pathways, tumorigenesis, and epigenetic reprogramming. Our findings revealed that GSK503 significantly increased CD4+ and CD8+ T cells in both splenocytes and colonic mucosa of treated mice compared to controls. Additionally, a preventive dose of GSK503 over 9 weeks notably reduced adenoma multiplicity, demonstrating its efficacy as a preventive modality. Single-cell RNA sequencing and molecular analyses showed activation of immune and apoptotic markers, along with a reduction in H3K27 methylation levels in colonic crypts. ChIP sequencing further revealed decreased levels of H3K27me3 and H3K4me1, while levels of the active enhancer marks H3K4me3 and H3K27Ac increased in treated mice. Collectively, these findings indicate that EZH2 inhibition enhances immune responses through epigenetic reprogramming in the genome of LS mice, establishing a promising framework for the clinical development of EZH2 inhibitors as a cancer prevention strategy for LS carriers.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414191","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
An intracellular complement system drives metabolic and proinflammatory reprogramming of vascular fibroblasts in pulmonary hypertension.
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-13 DOI: 10.1172/jci.insight.184141
Ram Raj Prasad, Sushil Kumar, Hui Zhang, Min Li, Cheng-Jun Hu, Suzette Riddle, Brittany A McKeon, M G Frid, Konrad Hoetzenecker, Slaven Crnkovic, Grazyna Kwapiszewska, Rubin M Tuder, Kurt R Stenmark

The complement system is central to the innate immune response, playing a critical role in pro-inflammatory and autoimmune diseases such as pulmonary hypertension (PH). Recent discoveries highlight the emerging role of intracellular complement, or the "complosome," in regulating cellular processes like glycolysis, mitochondrial dynamics, and inflammatory gene expression. This study investigates the hypothesis that intracellular complement proteins C3, CFB, and CFD are upregulated in PH fibroblasts (PH-Fibs) and drive their metabolic and inflammatory states, contributing to PH progression. Our results reveal a pronounced upregulation of CFD, CFB, and C3 in PH-Fibs from human and bovine models, both in vivo and in vitro. Elevated levels of C3 activation fragments, including C3b, C3d, and C3a, emphasize enhanced C3 activity. PH-Fibs exhibit notable metabolic reprogramming and increased pro-inflammatory mediators such as MCP1, SDF1, IL6, IL13, and IL33. Silencing CFD via shRNA reduced CFB activation and C3a production while normalizing glycolysis, tricarboxylic acid (TCA) cycle activity, and fatty acid metabolism. Metabolomic and gene expression analyses of CFD knockdown PH-Fibs revealed restored metabolic and inflammatory profiles, underscoring CFD's crucial role in these changes. This study emphasizes the crucial role of intracellular complement in PH pathogenesis, highlighting the potential for complement-targeted therapies in PH.

{"title":"An intracellular complement system drives metabolic and proinflammatory reprogramming of vascular fibroblasts in pulmonary hypertension.","authors":"Ram Raj Prasad, Sushil Kumar, Hui Zhang, Min Li, Cheng-Jun Hu, Suzette Riddle, Brittany A McKeon, M G Frid, Konrad Hoetzenecker, Slaven Crnkovic, Grazyna Kwapiszewska, Rubin M Tuder, Kurt R Stenmark","doi":"10.1172/jci.insight.184141","DOIUrl":"https://doi.org/10.1172/jci.insight.184141","url":null,"abstract":"<p><p>The complement system is central to the innate immune response, playing a critical role in pro-inflammatory and autoimmune diseases such as pulmonary hypertension (PH). Recent discoveries highlight the emerging role of intracellular complement, or the \"complosome,\" in regulating cellular processes like glycolysis, mitochondrial dynamics, and inflammatory gene expression. This study investigates the hypothesis that intracellular complement proteins C3, CFB, and CFD are upregulated in PH fibroblasts (PH-Fibs) and drive their metabolic and inflammatory states, contributing to PH progression. Our results reveal a pronounced upregulation of CFD, CFB, and C3 in PH-Fibs from human and bovine models, both in vivo and in vitro. Elevated levels of C3 activation fragments, including C3b, C3d, and C3a, emphasize enhanced C3 activity. PH-Fibs exhibit notable metabolic reprogramming and increased pro-inflammatory mediators such as MCP1, SDF1, IL6, IL13, and IL33. Silencing CFD via shRNA reduced CFB activation and C3a production while normalizing glycolysis, tricarboxylic acid (TCA) cycle activity, and fatty acid metabolism. Metabolomic and gene expression analyses of CFD knockdown PH-Fibs revealed restored metabolic and inflammatory profiles, underscoring CFD's crucial role in these changes. This study emphasizes the crucial role of intracellular complement in PH pathogenesis, highlighting the potential for complement-targeted therapies in PH.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414045","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
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