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JCI Insight

Minna Pekkinen, Paulien A Terhal, Lorenzo D Botto, Petra Henning, Riikka E Mäkitie, Paul Roschger, Amrita Jain, Matthijs Kol, Matti A Kjellberg, Eleftherios P Paschalis, Koen van Gassen, Mary Murray, Pinar Bayrak-Toydemir, Maria K Magnusson, Judith Jans, Mehran Kausar, John C Carey, Pentti Somerharju, Ulf H Lerner, Olkkonen M Vesa, Klaus Klaushofer, Joost Cm Holthuis, Outi Mäkitie
Mechanisms leading to osteoporosis are incompletely understood. Genetic disorders with skeletal fragility provide insight into metabolic pathways contributing to bone strength. We evaluated six families with rare skeletal phenotypes and osteoporosis by next-generation sequencing. In all families we identified a heterozygous variant in SGMS2, a gene prominently expressed in cortical bone and encoding the plasma membrane-resident sphingomyelin synthase SMS2. Four unrelated families shared the same nonsense variant c...
February 19, 2019: JCI Insight
Guoxin Zhang, Zhen Dong, Briana C Prager, Leo J Y Kim, Qiulian Wu, Ryan C Gimple, Xiuxing Wang, Shideng Bao, Petra Hamerlik, Jeremy N Rich
Glioblastoma represent universally lethal cancers, containing stem cell-like glioblastoma stem cells (GSCs). While neural stem cells (NSCs) are usually quiescent, single-cell studies suggest that proliferating glioblastoma cells reside in the GSC population. Interrogating in silico glioma databases for epigenetic regulators that correlate with cell cycle regulation, we identified the chromatin remodeler, HELLS, as a potential target in glioblastoma. GSCs preferentially expressed HELLS compared to their differentiated tumor progeny and non-malignant brain cells...
February 19, 2019: JCI Insight
Quan Liu, Gaelen K Dwyer, Yifei Zhao, Huihua Li, Lisa R Mathews, Anish Bhaswanth Chakka, Uma R Chandran, Jake A Demetris, John F Alcorn, Keven M Robinson, Luis A Ortiz, Bruce Pitt, Angus W Thomson, Ming-Hui Fan, Timothy R Billiar, Heth R Turnquist
Acute respiratory distress syndrome is an often fatal disease that develops after acute lung injury and trauma. How released tissue damage signals, or alarmins, orchestrate early inflammatory events is poorly understood. Herein we reveal that IL-33, an alarmin sequestered in the lung epithelium, is required to limit inflammation after injury due to an unappreciated capacity to mediate Foxp3+ Treg control of local cytokines and myeloid populations. Specifically, Il33-/- mice are more susceptible to lung damage-associated morbidity and mortality that is typified by augmented levels of the proinflammatory cytokines and Ly6Chi monocytes in the bronchoalveolar lavage fluid...
February 19, 2019: JCI Insight
Yu Jin Chung, Antao Luo, Kyung Chan Park, Aminah Loonat, Samira Lakhal-Littleton, Peter A Robbins, Pawel Swietach
Iron deficiency is present in approximately 50% of heart failure (HF) patients. Large multi-center trials have shown that treatment of iron deficiency with intravenous iron benefits HF patients, but the underlying mechanisms are not known. To investigate the actions of iron deficiency on the heart, mice were fed an iron-depleted diet and some received intravenous ferric carboxymaltose (FCM), an iron supplementation used clinically. Iron-deficient animals became anemic and had reduced ventricular ejection fraction measured by magnetic resonance imaging...
February 19, 2019: JCI Insight
Njabulo Ngwenyama, Ane M Salvador, Francisco Velázquez, Tania Nevers, Alexander Levy, Mark J Aronovitz, Andrew D Luster, Gordon S Huggins, Pilar Alcaide
Heart failure (HF) is associated in humans and mice with increased circulating levels of CXCL9 and CXCL10, chemokine ligands of the CXCR3 receptor, predominantly expressed on CD4+ T helper type 1 (Th1) cells. Chemokine engagement of receptors is required for T cell integrin activation and recruitment to sites of inflammation. Th1 cells drive adverse cardiac remodeling in pressure overload induced cardiac dysfunction, and mice lacking the integrin ligand ICAM-1 show defective T cell recruitment to the heart...
February 19, 2019: JCI Insight
Jonathan D Douros, Jingjing Niu, Sophia M Sdao, Trillian Gregg, Kelsey H Fisher-Wellman, Manish S Bharadwaj, Anthony Molina, Ramamani Arumugam, Mackenzie D Martin, Enrico Petretto, Matthew J Merrins, Mark A Herman, Jenny Tong, Jonathan E Campbell, David D'Alessio
Bariatric surgeries including vertical sleeve gastrectomy (VSG) ameliorate obesity and diabetes. Weight-loss and accompanying increases to insulin sensitivity contribute to improved glycemia after surgery, however, studies in humans also suggest weight-independent actions of bariatric procedures to lower blood glucose, possibly by improving insulin secretion. To evaluate this hypothesis, we compared VSG operated mice with pair-fed, sham-surgical controls (PF-Sham) 2 weeks after surgery. This paradigm yielded similar post-operative body weight and insulin sensitivity between VSG and calorically restricted PF-Sham animals...
February 19, 2019: JCI Insight
Mohammad Haque, Fengyang Lei, Xiaofang Xiong, Jugal Kishore Das, Xingcong Ren, Deyu Fang, Shahram Salek-Ardakani, Jin-Ming Yang, Jianxun Song
The auto antigen (Ag)-specific regulatory T cells (Tregs) from pluripotent stem cells (PSCs), i.e., PSC-Tregs, have the ability to suppress autoimmunity. PSC-Tregs can be programmed to be tissue-associated and to infiltrate into local inflamed tissues to suppress autoimmune responses after adoptive transfer. Nevertheless, the mechanisms by which the auto Ag-specific PSC-Tregs suppress the autoimmune response remain to be fully elucidated. In this study, we generated the functional auto Ag-specific Tregs from the induced PSC (iPSCs), i...
February 19, 2019: JCI Insight
Yan Geng, Xue Liu, Jiurong Liang, David M Habiel, Kulur Vrishika, Ana Lucia Coelho, Nan Deng, Ting Xie, Yizhou Wang, Ningshan Liu, Guanling Huang, Adrianne Kurkciyan, Zhenqiu Liu, Jie Tang, Cory M Hogaboam, Dianhua Jiang, Paul W Noble
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with unremitting extracellular matrix deposition, leading to a distortion of pulmonary architecture and impaired gas exchange. Fibroblasts from IPF patients acquire an invasive phenotype that is essential for progressive fibrosis. Here, we performed RNA-seq analysis on invasive and non-invasive fibroblasts and found that the immune checkpoint ligand CD274 (PD-L1) was up-regulated on invasive lung fibroblasts and was required for the invasive phenotype of lung fibroblasts, is regulated by P53 and FAK, and drives lung fibrosis in a humanized IPF model in mice...
February 14, 2019: JCI Insight
Yao Xiong, Kenneth C Bedi, Simon Berritt, Thomas G Brooks, Bennette K Attipoe, Kevin Wang, Kenneth B Margulies, Jeffrey Field
About one-third of dilated cardiomyopathy (DCM) cases are caused by mutations in sarcomere or cytoskeletal proteins. Yet treating the cytoskeleton directly is not possible because drugs that bind to actin are not well tolerated. Mutations in the actin binding protein CAP2 can cause DCM and knockout mice, either whole body (CAP2 KO) or cardiomyocyte-specific knockouts (CAP2 CKO), develop DCM with cardiac conduction disease. RNA-seq analysis of CAP2 KO hearts and isolated cardiomyocytes revealed over-activation of fetal genes including serum response factor (SRF) regulated genes such as Myl9 and Acta2 prior to the emergence of cardiac disease...
February 14, 2019: JCI Insight
Jason R Mock, Catherine F Dial, Miriya K Tune, Dustin L Norton, Jessica R Martin, John C Gomez, Robert S Hagan, Hong Dang, Claire M Doerschuk
Recovery from acute lung injury (ALI) is an active process. Foxp3+ regulatory T cells (Tregs) contribute to recovery from ALI through modulating immune responses and enhancing alveolar epithelial proliferation and tissue repair. The current study investigates Treg transcriptional profiles during resolution of ALI in mice. Tregs from either lung or splenic tissue were isolated from uninjured mice or mice recovering from ALI and then examined for differential gene expression between these conditions. In mice with ALI, Tregs isolated from the lungs had hundreds of differentially expressed transcripts compared to those from the spleen, indicating that organ-specificity and microenvironment are critical in Treg function...
February 12, 2019: JCI Insight
Nicholas Aj Dawson, Caroline Lamarche, Romy E Hoeppli, Peter Bergqvist, Vivian Fung, Emma McIver, Qing Huang, Jana Gillies, Madeleine Speck, Paul C Orban, Jonathan W Bush, Majid Mojibian, Megan K Levings
Chimeric antigen receptor (CAR) technology can be used to engineer the antigen-specificity of regulatory T cells (Tregs) and improve their potency as an adoptive cell therapy in multiple disease models. As synthetic receptors, CARs carry the risk of immunogenicity, particularly when derived from non-human antibodies. Using an HLA-A*02:01-specific CAR (A2-CAR) encoding a single-chain Fv derived from a mouse antibody, we developed a panel of 20 humanized (h)A2-CARs. Systematic testing demonstrated variations in expression, ability to bind HLA-A*02:01, and stimulate human Treg suppression in vitro...
February 12, 2019: JCI Insight
Michael W O'Reilly, Connar Sj Westgate, Catherine Hornby, Hannah Botfield, Angela E Taylor, Keira Markey, James L Mitchell, William J Scotton, Susan P Mollan, Andreas Yiangou, Carl Jenkinson, Lorna C Gilligan, Mark Sherlock, James Gibney, Jeremy W Tomlinson, Gareth G Lavery, David J Hodson, Wiebke Arlt, Alexandra J Sinclair
Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated intracranial pressure frequently manifesting with chronic headaches and visual loss. Similar to polycystic ovary syndrome (PCOS), IIH predominantly affects obese women of reproductive age. In this study, we comprehensively examined the systemic and cerebrospinal fluid (CSF) androgen metabolome in women with IIH in comparison to sex-, body mass index- and age-matched control groups with either simple obesity and PCOS, i...
February 12, 2019: JCI Insight
Ruru Guo, Ting Zhang, Xinyu Meng, Zhen Lin, Jinran Lin, Yu Gong, Xuesong Liu, Yuetian Yu, Guilin Zhao, Xianting Ding, Xiaoxiang Chen, Liangjing Lu
Psoriasis (PS) is a systemic, immune-mediated inflammatory disorder. However, the whole lymphocyte compartment and the potential pathologies of PS have not been fully characterized. In the present study, we examined whole lymphocyte subsets and signal transduction proteins using high-dimensional single-cell mass cytometry and a bioinformatics pipeline for an in-depth characterization of the immune cell subsets and protein profiles involved in pathways in the peripheral blood of patients with PS. We identified 15 major immune cell populations in T cell lineages, and characterized various CD3+CD4+T helper and CD3+CD8+T cytotoxic cell populations simultaneously across 24 leukocyte markers and 7 proteins related to the signal transduction pathways...
February 12, 2019: JCI Insight
Ariele L Greenfield, Ravi Dandekar, Akshaya Ramesh, Erica L Eggers, Hao Wu, Sarah Laurent, William Harkin, Natalie S Pierson, Martin S Weber, Roland G Henry, Antje Bischof, Bruce Ac Cree, Stephen L Hauser, Michael R Wilson, H-Christian von Büdingen
B-cells are key contributors to chronic autoimmune pathology in multiple sclerosis (MS). Clonally related B-cells exist in the cerebrospinal fluid (CSF), meninges, and central nervous system (CNS) parenchyma of MS patients. We sought to investigate the presence of clonally related B-cells over time by performing immunoglobulin heavy chain variable region repertoire sequencing on B-cells from longitudinally collected blood and CSF samples of MS patients (n=10). All patients were untreated at the time of the initial sampling; the majority (n=7) were treated with immune modulating therapies 1...
February 12, 2019: JCI Insight
Masanobu Kawai, Saori Kinoshita, Miwa Yamazaki, Keiko Yamamoto, Clifford J Rosen, Shigeki Shimba, Keiichi Ozono, Toshimi Michigami
The circadian clock network is an evolutionally conserved system involved in the regulation of metabolic homeostasis; however, its impacts on skeletal metabolism remain largely unknown. We herein demonstrated that circadian clock network in the intestines plays pivotal roles in skeletal metabolism such that the lack of Bmal1 gene in the intestines (Bmal1Int-/- mice) caused bone loss with bone resorption being activated and bone formation suppressed. Mechanistically, Clock interaction with Vitamin D receptor (Vdr) accelerated its binding to VDR response element by enhancing histone acetylation in a circadian-dependent manner, and this was lost in Bmal1Int-/- mice because nuclear translocation of Clock required the presence of Bmal1...
February 7, 2019: JCI Insight
Anne M Pesenacker, Virginia Chen, Jana Gillies, Cate Speake, Ashish K Marwaha, Annika C Sun, Samuel Chow, Rusung Tan, Thomas Elliott, Jan P Dutz, Scott J Tebbutt, Megan K Levings
BACKGROUND: Multiple therapeutic strategies to restore immune regulation and slow type 1 diabetes (T1D) progression are in development and testing. A major challenge has been defining biomarkers to prospectively identify subjects likely to benefit from immunotherapy and/or measure intervention effects. We previously found that compared to healthy controls, Tregs from children with new-onset T1D have an altered Treg gene signature (TGS), suggesting this could be an immunoregulatory biomarker...
February 7, 2019: JCI Insight
Kelly L Singel, Tiffany R Emmons, Anm Nazmul H Khan, Paul C Mayor, Shichen Shen, Jerry T Wong, Kayla Morrell, Kevin H Eng, Jaron Mark, Richard B Bankert, Junko Matsuzaki, Richard C Koya, Anna M Blom, Kenneth R McLeish, Jun Qu, Sanjay Ram, Kirsten B Moysich, Scott I Abrams, Kunle Odunsi, Emese Zsiros, Brahm H Segal
Epithelial ovarian cancer (EOC) often presents with metastases and ascites. Granulocytic myeloid-derived suppressor cells are an immature population that impairs anti-tumor immunity. Since suppressive granulocytes in the ascites of patients with newly diagnosed EOC were morphologically mature, we hypothesized that PMN were rendered suppressive in the tumor microenvironment. Circulating PMN from patients were not suppressive, but acquired a suppressor phenotype (defined as ≥ 1 log10 reduction of anti-CD3/CD28-stimulated T cell proliferation) after ascites supernatant exposure...
February 7, 2019: JCI Insight
Ellis Y Kim, David Y Barefield, Andy H Vo, Anthony M Gacita, Emma J Schuster, Eugene J Wyatt, Janel L Davis, Biqin Dong, Cheng Sun, Patrick Page, Lisa Dellefave-Castillo, Alexis Demonbreun, Hao F Zhang, Elizabeth M McNally
Myotonic dystrophy (DM) is the most common autosomal dominant muscular dystrophy and encompasses both skeletal muscle and cardiac complications. Myotonic dystrophy is nucleotide repeat expansion disorder in which type 1 (DM1) is due to a trinucleotide repeat expansion on chromosome 19 and type 2 (DM2) arises from a tetranucleotide repeat expansion on chromosome 3. Developing representative models of myotonic dystrophy in animals has been challenging due to instability of nucleotide repeat expansions, especially for DM2 which is characterized by nucleotide repeat expansions often greater than 5000 copies...
February 7, 2019: JCI Insight
Xiuxia Zhou, Carol L Kinlough, Rebecca P Hughey, Mingzhu Jin, Hideki Inoue, Emily Etling, Brian D Modena, Naftali Kaminski, Eugene R Bleecker, Deborah A Meyers, Nizar N Jarjour, John B Trudeau, Fernando Holguin, Anuradha Ray, Sally E Wenzel
Although Type-2 (T2) induced epithelial dysfunction is likely to profoundly alter epithelial differentiation and repair in asthma, the mechanisms for these effects are poorly understood. A role for specific mucins, heavily N-glycosylated epithelial glycoproteins, in orchestrating epithelial cell fate in response to T2 stimuli has not previously been investigated. Levels of a sialylated MUC4β isoform were found to be increased in airway specimens from asthmatic patients, in association with T2 inflammation...
February 7, 2019: JCI Insight
Jeewon Garcia-So, Xinwen Zhang, Xiaohua Yang, Mara Roxana Rubinstein, De Yu Mao, Jan Kitajewski, Kang Liu, Yiping W Han
Fusobacterium nucleatum is an oral anaerobe prevalent in intrauterine infection associated with a wide spectrum of adverse pregnancy outcomes. We demonstrate here that F. nucleatum triggers placental inflammation through maternal, rather than paternal, TLR4-mediated signaling. Elimination of TLR4 from maternal endothelial cells alleviated placental inflammation and reduced fetal and neonatal death, while elimination of TLR4 in the hematopoietic cells had no effect. The placental inflammatory response followed a spatiotemporal pattern, with NF-κB activation observed first in the maternal endothelial cells and then in the decidual cells surrounding the endothelium, followed by induction of inflammatory cytokines and chemokines...
February 7, 2019: JCI Insight
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