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Özden C, Afacan B, İlhan HA, Köse T, Emingil G. Oral biofluid levels of Activin-A and interleukin-1beta in stage III periodontitis. Clin Oral Investig 2024; 29:7. [PMID: 39656274 DOI: 10.1007/s00784-024-06088-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 11/28/2024] [Indexed: 02/07/2025]
Abstract
OBJECTIVES Activin-A belongs to the transforming growth factor-beta superfamily and is a multifunctional cytokine that plays a role in inflammation, immune response, tissue repair and regeneration. Proinflammatory cytokine interleukin-1beta (IL-1β) can increase Activin-A expression in various cell types. This study aims to evaluate gingival crevicular fluid (GCF) and salivary Activin-A and IL-β levels in stage III periodontitis. MATERIALS AND METHODS 23 patients with stage III periodontitis, 26 with gingivitis and 26 periodontally healthy individuals were included. Full-mouth clinical periodontal indices were recorded, unstimulated whole saliva and GCF samples were obtained, Activin-A and IL-1β total amounts were determined by ELISA. Statistical comparisons were performed using non-parametric tests. Receiver operating characteristics curve was used for estimating the area under the curve (AUC). RESULTS Periodontitis group exhibited significantly lower GCF Activin-A levels but higher IL-1β levels than the periodontally healthy group (p < 0.05). Gingivitis group had similar GCF Activin-A and IL-1β levels to the periodontitis and periodontally healthy groups (p > 0.05). Salivary Activin-A and IL-1β concentrations were similar among study groups (p > 0.05). GCF Activin-A level showed an excellent diagnostic performance (an AUC value of 0.82 with 87% sensitivity) to discriminate periodontitis from periodontal health. CONCLUSIONS For the first time, this study demonstrated oral biofluid levels of Activin-A in periodontal health and diseases. Within the limits of the study, it might be suggested that diseased sites in periodontitis are associated with reduced Activin-A and increased IL-1β levels in GCF. CLINICAL RELEVANCE Reduced GCF Activin-A levels and the accompanying increase in IL-1β might be associated with diseased sites in stage III periodontitis.
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Affiliation(s)
- Can Özden
- Department of Periodontology, Faculty of Dentistry, Aydın Adnan Menderes University, Aydın, Turkey
| | - Beral Afacan
- Department of Periodontology, Faculty of Dentistry, Aydın Adnan Menderes University, Aydın, Turkey.
| | - Harika Atmaca İlhan
- Section of Molecular Biology, Department of Biology, Faculty of Science and Letters, Manisa Celal Bayar University, Manisa, Turkey
| | - Timur Köse
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, İzmir Ege University, İzmir, Turkey
| | - Gülnur Emingil
- Department of Periodontology, Faculty of Dentistry, İstinye University, İstanbul, Turkey
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Madonna R, Biondi F. Sotatercept: New drug on the horizon of pulmonary hypertension. Vascul Pharmacol 2024; 157:107442. [PMID: 39571875 DOI: 10.1016/j.vph.2024.107442] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 11/03/2024] [Accepted: 11/14/2024] [Indexed: 11/26/2024]
Abstract
Sotatercept (brand name WINREVAIR, developed by Merck) is an activin receptor type IIA-Fc (ActRIIA-Fc), working by sequestering free activins. Sotatercept restores the balance between the activin proliferative pathway and the bone morphogenic protein (BMP) antiproliferative pathway in the pulmonary arterial cirulation. Sotatercept recently received approval in the USA and in Europe for the treatment of adults with pulmonary arterial hypertension (PAH) Group 1, on top of background PAH therapy to increase exercise capacity, improve WHO functional class and reduce the risk of clinical worsening events. Nevertheless, several studies are ongoing to investigate the potential adverse reactions of the drug especially at the haematological level. We provide an overview of the clinical and preclinical evidence of the targeting the activing pathway through sotatercept on the treatment of PAH. We also discuss what other possibilities there are for the application of sotatercept in the setting of pulmonary hypertension other than PAH Group 1.
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Affiliation(s)
- Rosalinda Madonna
- Department of Surgical, Medical and Molecular Pathology and Critical Area, Cardiology Division, University of Pisa, Pisa, Italy.
| | - Filippo Biondi
- Department of Surgical, Medical and Molecular Pathology and Critical Area, Cardiology Division, University of Pisa, Pisa, Italy
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3
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Pei Y, Liu F, Zhao Y, Lin H, Huang X. Role of hedgehog signaling in the pathogenesis and therapy of heterotopic ossification. Front Cell Dev Biol 2024; 12:1454058. [PMID: 39364140 PMCID: PMC11447292 DOI: 10.3389/fcell.2024.1454058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 09/05/2024] [Indexed: 10/05/2024] Open
Abstract
Heterotopic ossification (HO) is a pathological process that generates ectopic bone in soft tissues. Hedgehog signaling (Hh signaling) is a signaling pathway that plays an important role in embryonic development and involves three ligands: sonic hedgehog (Shh), Indian hedgehog (Ihh) and desert hedgehog (Dhh). Hh signaling also has an important role in skeletal development. This paper discusses the effects of Hh signaling on the process of HO formation and describes several signaling molecules that are involved in Hh-mediated processes: parathyroid Hormone-Related Protein (PTHrP) and Fkbp10 mediate the expression of Hh during chondrogenesic differentiation. Extracellular signal-regulated kinase (ERK), GNAs and Yes-Associated Protein (YAP) interact with Hh signaling to play a role in osteogenic differentiation. Runt-Related Transcription Factor 2 (Runx2), Mohawk gene (Mkx) and bone morphogenetic protein (BMP) mediate Hh signaling during both chondrogenic and osteogenic differentiation. This paper also discusses possible therapeutic options for HO, lists several Hh inhibitors and explores whether they could serve as emerging targets for the treatment of HO.
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Affiliation(s)
- Yiran Pei
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Fangzhou Liu
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Yike Zhao
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Hui Lin
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xiaoyan Huang
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
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Sun L, Jin Y, Nishio M, Watanabe M, Kamakura T, Nagata S, Fukuda M, Maekawa H, Kawai S, Yamamoto T, Toguchida J. Oxidative phosphorylation is a pivotal therapeutic target of fibrodysplasia ossificans progressiva. Life Sci Alliance 2024; 7:e202302219. [PMID: 38365425 PMCID: PMC10875110 DOI: 10.26508/lsa.202302219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 01/31/2024] [Accepted: 02/07/2024] [Indexed: 02/18/2024] Open
Abstract
Heterotopic ossification (HO) is a non-physiological bone formation where soft tissue progenitor cells differentiate into chondrogenic cells. In fibrodysplasia ossificans progressiva (FOP), a rare genetic disease characterized by progressive and systemic HO, the Activin A/mutated ACVR1/mTORC1 cascade induces HO in progenitors in muscle tissues. The relevant biological processes aberrantly regulated by activated mTORC1 remain unclear, however. RNA-sequencing analyses revealed the enrichment of genes involved in oxidative phosphorylation (OXPHOS) during Activin A-induced chondrogenesis of mesenchymal stem cells derived from FOP patient-specific induced pluripotent stem cells. Functional analyses showed a metabolic transition from glycolysis to OXPHOS during chondrogenesis, along with increased mitochondrial biogenesis. mTORC1 inhibition by rapamycin suppressed OXPHOS, whereas OXPHOS inhibitor IACS-010759 inhibited cartilage matrix formation in vitro, indicating that OXPHOS is principally involved in mTORC1-induced chondrogenesis. Furthermore, IACS-010759 inhibited the muscle injury-induced enrichment of fibro/adipogenic progenitor genes and HO in transgenic mice carrying the mutated human ACVR1. These data indicated that OXPHOS is a critical downstream mediator of mTORC1 signaling in chondrogenesis and therefore is a potential FOP therapeutic target.
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Affiliation(s)
- Liping Sun
- Department of Regeneration Sciences and Engineering, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yonghui Jin
- Department of Regeneration Sciences and Engineering, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Megumi Nishio
- Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Makoto Watanabe
- Life Science Research Center, Technology Research Laboratory, Shimadzu Corporation, Kyoto, Japan
| | - Takeshi Kamakura
- Department of Regeneration Sciences and Engineering, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Sanae Nagata
- Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Masayuki Fukuda
- Department of Regeneration Sciences and Engineering, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Hirotsugu Maekawa
- Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Shunsuke Kawai
- Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Takuya Yamamoto
- Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
- Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan
- Medical-risk Avoidance Based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project, Kyoto, Japan
| | - Junya Toguchida
- Department of Regeneration Sciences and Engineering, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
- Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
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5
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Zaman S, Gorelick F. Acute pancreatitis: pathogenesis and emerging therapies. JOURNAL OF PANCREATOLOGY 2024; 7:10-20. [PMID: 38524855 PMCID: PMC10959536 DOI: 10.1097/jp9.0000000000000168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 12/25/2023] [Indexed: 03/26/2024] Open
Abstract
Acute pancreatitis is a severe inflammatory disorder with limited treatment options. Improved understanding of disease mechanisms has led to new and potential therapies. Here we summarize what we view as some of the most promising new therapies for treating acute pancreatitis, emphasizing the rationale of specific treatments based on disease mechanisms. Targeted pharmacologic interventions are highlighted. We explore potential treatment benefits and risks concerning reducing acute injury, minimizing complications, and improving long-term outcomes. Mechanisms associated with acute pancreatitis initiation, perpetuation, and reconstitution are highlighted, along with potential therapeutic targets and how these relate to new treatments.
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Affiliation(s)
- Saif Zaman
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511
| | - Fred Gorelick
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511
- Veteran’s Administration Healthcare System, West Haven, CT 06516
- Department of Cell Biology, Yale School of Medicine, New Haven, CT 06511
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Jin BR, Kim HJ, Na JH, Lee WK, An HJ. Targeting benign prostate hyperplasia treatments: AR/TGF-β/NOX4 inhibition by apocynin suppresses inflammation and proliferation. J Adv Res 2024; 57:135-147. [PMID: 37061215 PMCID: PMC10918329 DOI: 10.1016/j.jare.2023.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/19/2023] [Accepted: 04/10/2023] [Indexed: 04/17/2023] Open
Abstract
INTRODUCTION Apocynin (Apo), an NADPH oxidase (NOX) inhibitor, has been widely used to treat various inflammatory diseases. However, the therapeutic effects of Apo on benign prostatic hyperplasia (BPH), a multifactorial disease associated with chronic inflammation and hormone imbalance, remain unknown. OBJECTIVES The link between androgen signaling, reactive oxygen species (ROS), and prostate cell proliferation may contribute to the pathogenesis of BPH; therefore, the aim of this study was to identify the specific signaling pathway involved and to demonstrate whether the anti-oxidant Apo plays a role in the prevention and treatment of BPH. METHODS Ingenuity pathway analysis and si-RNA transfection were conducted to demonstrate the androgen receptor (AR) and NOX4 linkage in BPH. Pathological markers of BPH were measured by H&E staining, immunoblotting, ELISA, qRT-PCR, and immunofluorescence to examine the effect of Apo. Rats stimulated with testosterone and BPH-1 cells were used as BPH models. RESULTS AR and NOX4 network-mediated oxidative stress was upregulated in the BPH model. Next, we examined the effects of Apo on oxidative stress and chronic prostatic inflammation in BPH mouse models. In a testosterone-induced BPH rat model, Apo alleviated pathological prostate enlargement and suppressed androgen/AR signaling. Apo suppressed the upregulation of proinflammatory markers and promoted the expression of anti-oxidant factors. Furthermore, Apo regulated the TGF-β/Glut9/activin pathway and macrophage programming. In BPH-1 cells, Apo suppressed AR-mediated proliferation and upregulation of TGFB and NOX4 expression by alleviating oxidative stress. Apo activated anti-oxidant and anti-inflammatory systems and regulated macrophage polarization in BPH-1 cells. AR knockdown partially abolished the beneficial effects of Apo in prostate cells, indicating AR-dependent effects of Apo. CONCLUSION In contrast with existing BPH therapies, Apo may provide a new application for prostatic disease treatment, especially for BPH, by targeting the AR/TGF-β/NOX4 signaling pathway.
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Affiliation(s)
- Bo-Ram Jin
- Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
| | - Hyo-Jung Kim
- Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
| | - Jung-Hyun Na
- School of Biopharmaceutical and Medical Sciences, Sungshin Women's University, Seoul, Republic of Korea.
| | - Won-Kyu Lee
- New Drug Development Center, Osong Medical Innovation Foundation, Cheongju, Chungcheongbuk-do, 28160, Republic of Korea.
| | - Hyo-Jin An
- Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Integrated Drug Development and Natural Products, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.
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7
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Juengel JL, Reader KL, Maclean PH, Quirke LD, Zellhuber-McMillan S, Haack NA, Heiser A. The role of the oviduct environment in embryo survival. Reprod Fertil Dev 2024; 36:RD23171. [PMID: 38402905 DOI: 10.1071/rd23171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 02/01/2024] [Indexed: 02/27/2024] Open
Abstract
CONTEXT Declining fertility is an issue in multiple mammalian species. As the site of fertilisation and early embryo development, the oviduct plays a critical role in embryo survival, yet there is a paucity of information on how the oviduct regulates this process. AIMS We hypothesised that differences in steroid hormone signalling and/or immune function would be observed in a model of poor embryo survival, the peripubertal ewe. METHODS We examined expression of steroid hormones in systemic circulation, oviductal expression of oestrogen receptorαand genes important in steroid hormone signalling, and immune function in pregnant and cyclic peripubertal and adult ewes on day 3 after oestrus. KEY RESULTS Concentrations of progesterone, but not oestradiol, were decreased in the peripubertal ewe compared to the adult ewe. Oestrogen receptorαprotein expression was increased in the peripubertal ewe, but pathway analysis of gene expression revealed downregulation of the oestrogen signalling pathway compared to the adult ewe. Differential expression of several genes involved in immune function between the peripubertal and adult ewe was consistent with an unfavourable oviductal environment in the peripubertal ewe lamb. Oestradiol concentration was positively correlated with the expression of multiple genes involved in the regulation of immune function. CONCLUSIONS Differences in the immune environment of the oviduct, potentially linked to differential modulation by steroid hormones, may partially underly the poor fertilisation and early embryo survival observed in the peripubertal ewe. IMPLICATIONS A unfavourable oviductal environment may play an important role in limiting reproductive success.
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Affiliation(s)
- Jennifer L Juengel
- Agricultural Systems and Reproduction, AgResearch Ltd, Invermay Agricultural Centre, Mosgiel 9092, New Zealand
| | - Karen L Reader
- Department of Pathology, University of Otago, Dunedin 9016, New Zealand
| | - Paul H Maclean
- Bioinformatics and Statistics, AgResearch Ltd, Grasslands Research Centre, Private Bag 11008, Palmerston North, New Zealand
| | - Laurel D Quirke
- Agricultural Systems and Reproduction, AgResearch Ltd, Invermay Agricultural Centre, Mosgiel 9092, New Zealand
| | | | - Neville A Haack
- Animal Health Solutions, Hopkirk Research Institute, AgResearch Ltd, Private Bag 11008, Palmerston North 4442, New Zealand
| | - Axel Heiser
- Animal Health Solutions, Hopkirk Research Institute, AgResearch Ltd, Private Bag 11008, Palmerston North 4442, New Zealand
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8
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Chen L, Zhong S, Wang Y, Wang X, Liu Z, Hu G. Bmp4 in Zebrafish Enhances Antiviral Innate Immunity through p38 MAPK (Mitogen-Activated Protein Kinases) Pathway. Int J Mol Sci 2023; 24:14444. [PMID: 37833891 PMCID: PMC10572509 DOI: 10.3390/ijms241914444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/17/2023] [Accepted: 09/19/2023] [Indexed: 10/15/2023] Open
Abstract
Bone morphogenetic proteins (BMPs) are a group of structurally and functionally related signaling molecules that comprise a subfamily, belonging to the TGF-β superfamily. Most BMPs play roles in the regulation of embryonic development, stem cell differentiation, tumor growth and some cardiovascular and cerebrovascular diseases. Although evidence is emerging for the antiviral immunity of a few BMPs, more BMPs are needed to determine whether this function is universal. Here, we identified the zebrafish bmp4 ortholog, whose expression is up-regulated through challenge with grass carp reovirus (GCRV) or its mimic poly(I:C). The overexpression of bmp4 in epithelioma papulosum cyprini (EPC) cells significantly decreased the viral titer of GCRV-infected cells. Moreover, compared to wild-type zebrafish, viral load and mortality were significantly increased in both larvae and adults of bmp4-/- mutant zebrafish infected with GCRV virus. We further demonstrated that Bmp4 promotes the phosphorylation of Tbk1 and Irf3 through the p38 MAPK pathway, thereby inducing the production of type I IFNs in response to virus infection. These data suggest that Bmp4 plays an important role in the host defense against virus infection. Our study expands the understanding of BMP protein functions and opens up new targets for the control of viral infection.
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Affiliation(s)
| | | | | | | | - Zhenhui Liu
- College of Marine Life Science, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China; (L.C.); (S.Z.); (Y.W.); (X.W.)
| | - Guobin Hu
- College of Marine Life Science, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China; (L.C.); (S.Z.); (Y.W.); (X.W.)
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Hatamzade Esfahani N, Day AS. The Role of TGF-β, Activin and Follistatin in Inflammatory Bowel Disease. GASTROINTESTINAL DISORDERS 2023; 5:167-186. [DOI: 10.3390/gidisord5020015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/10/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition predominantly affecting the gastrointestinal (GI) tract. An increasing prevalence of IBD has been observed globally. The pathogenesis of IBD includes a complex interplay between the intestinal microbiome, diet, genetic factors and immune responses. The consequent imbalance of inflammatory mediators ultimately leads to intestinal mucosal damage and defective repair. Growth factors, given their specific roles in maintaining the homeostasis and integrity of the intestinal epithelium, are of particular interest in the setting of IBD. Furthermore, direct targeting of growth factor signalling pathways involved in the regeneration of the damaged epithelium and the regulation of inflammation could be considered as therapeutic options for individuals with IBD. Several members of the transforming growth factor (TGF)-β superfamily, particularly TGF-β, activin and follistatin, are key candidates as they exhibit various roles in inflammatory processes and contribute to maintenance and homeostasis in the GI tract. This article aimed firstly to review the events involved in the pathogenesis of IBD with particular emphasis on TGF-β, activin and follistatin and secondly to outline the potential role of therapeutic manipulation of these pathways.
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Affiliation(s)
| | - Andrew S. Day
- Paediatric Department, University of Otago Christchurch, Christchurch 8140, New Zealand
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Preechanukul A, Yimthin T, Tandhavanant S, Brummaier T, Chomkatekaew C, Das S, Syed Ahamed Kabeer B, Toufiq M, Rinchai D, West TE, Chaussabel D, Chantratita N, Garand M. Abundance of ACVR1B transcript is elevated during septic conditions: Perspectives obtained from a hands-on reductionist investigation. Front Immunol 2023; 14:1072732. [PMID: 37020544 PMCID: PMC10067751 DOI: 10.3389/fimmu.2023.1072732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 03/01/2023] [Indexed: 04/07/2023] Open
Abstract
Sepsis is a complex heterogeneous condition, and the current lack of effective risk and outcome predictors hinders the improvement of its management. Using a reductionist approach leveraging publicly available transcriptomic data, we describe a knowledge gap for the role of ACVR1B (activin A receptor type 1B) in sepsis. ACVR1B, a member of the transforming growth factor-beta (TGF-beta) superfamily, was selected based on the following: 1) induction upon in vitro exposure of neutrophils from healthy subjects with the serum of septic patients (GSE49755), and 2) absence or minimal overlap between ACVR1B, sepsis, inflammation, or neutrophil in published literature. Moreover, ACVR1B expression is upregulated in septic melioidosis, a widespread cause of fatal sepsis in the tropics. Key biological concepts extracted from a series of PubMed queries established indirect links between ACVR1B and "cancer", "TGF-beta superfamily", "cell proliferation", "inhibitors of activin", and "apoptosis". We confirmed our observations by measuring ACVR1B transcript abundance in buffy coat samples obtained from healthy individuals (n=3) exposed to septic plasma (n = 26 melioidosis sepsis cases)ex vivo. Based on our re-investigation of publicly available transcriptomic data and newly generated ex vivo data, we provide perspective on the role of ACVR1B during sepsis. Additional experiments for addressing this knowledge gap are discussed.
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Affiliation(s)
- Anucha Preechanukul
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Thatcha Yimthin
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Sarunporn Tandhavanant
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Tobias Brummaier
- Swiss Tropical and Public Health Institute, Basel, Switzerland
- University of Basel, Basel, Switzerland
| | - Chalita Chomkatekaew
- Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Sukanta Das
- Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | | | - Mohammed Toufiq
- Systems Biology and Immunology Department, Sidra Medicine, Doha, Qatar
| | - Darawan Rinchai
- Systems Biology and Immunology Department, Sidra Medicine, Doha, Qatar
| | - T. Eoin West
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, United States
- Department of Global Health, University of Washington, Seattle, WA, United States
| | - Damien Chaussabel
- Systems Biology and Immunology Department, Sidra Medicine, Doha, Qatar
| | - Narisara Chantratita
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Mathieu Garand
- Systems Biology and Immunology Department, Sidra Medicine, Doha, Qatar
- Division of Pediatric Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MI, United States
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Nagayama I, Takayanagi K, Hasegawa H, Maeshima A. Tubule-Derived Follistatin Is Increased in the Urine of Rats with Renal Ischemia and Reflects the Severity of Acute Tubular Damage. Cells 2023; 12:801. [PMID: 36899937 PMCID: PMC10000847 DOI: 10.3390/cells12050801] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Activin A, a member of the TGF-beta superfamily, is a negative regulator of tubular regeneration after renal ischemia. Activin action is controlled by an endogenous antagonist, follistatin. However, the role of follistatin in the kidney is not fully understood. In the present study, we examined the expression and localization of follistatin in normal and ischemic rat kidneys and measured urinary follistatin in rats with renal ischemia to assess whether urinary follistatin could serve as a biomarker for acute kidney injury. Using vascular clamps, renal ischemia was induced for 45 min in 8-week-old male Wistar rats. In normal kidneys, follistatin was localized in distal tubules of the cortex. In contrast, in ischemic kidneys, follistatin was localized in distal tubules of both the cortex and outer medulla. Follistatin mRNA was mainly present in the descending limb of Henle of the outer medulla in normal kidneys but was upregulated in the descending limb of Henle of both the outer and inner medulla after renal ischemia. Urinary follistatin, which was undetectable in normal rats, was significantly increased in ischemic rats and peaked 24 h after reperfusion. There was no correlation between urinary follistatin and serum follistatin. Urinary follistatin levels were increased according to ischemic duration and were significantly correlated with the follistatin-positive area as well as the acute tubular damage area. These results suggest that follistatin normally produced by renal tubules increases and becomes detectable in urine after renal ischemia. Urinary follistatin might be useful to assess the severity of acute tubular damage.
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Affiliation(s)
| | | | | | - Akito Maeshima
- Department of Nephrology and Hypertension, Saitama Medical Center, Saitama Medical University, Kawagoe 350-8550, Japan
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Pant S, Bhati T, Dimri A, Arora R, Siraj F, Raisuddin S, Rastogi S. Chlamydia trachomatis infection regulates the expression of tetraspanins, activin-A, and inhibin-A in tubal ectopic pregnancy. Pathog Dis 2023; 81:ftad018. [PMID: 37480234 DOI: 10.1093/femspd/ftad018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/17/2023] [Accepted: 07/20/2023] [Indexed: 07/23/2023] Open
Abstract
Mechanism of Chlamydia trachomatis causing tubal ectopic pregnancy (EP) is not well understood. Tetraspanins (tspans), activin-A, and inhibin-A might play a role in the development of pathological conditions leading to EP. The study aimed to elucidate the expression of tspans, activin-A, and inhibin-A with a role of associated cytokines in C. trachomatis-associated EP and analyze interacting partners of DEGs, with an expression of a few important interacting genes. Fallopian tissue and serum were collected from 100 EP (Group I) and 100 controls (Group II) from SJH, New Delhi, India. Detection of C. trachomatis was done by polymerase chain reaction (PCR) and IgG antibodies were detected by enzyme-linked immunosorbent assay. Expression of tspans, activin-A, inhibin-A, and cytokines was analyzed by real time (RT)-PCR and their interacting genes were assessed by STRING. Expression of few disease-associated interacting genes was studied by RT-PCR. A total of 29% (Group I) were C. trachomatis positive. Tspans and activin-A were significantly upregulated, while inhibin-A was significantly downregulated in Group Ia. ITGA1, TLR-2, ITGB2, and Smad-3 were a few interacting genes. Expression of ITGA1, TLR-2, and Smad-3 was significantly upregulated in C. trachomatis-positive EP. Results suggested dysregulated tspans, activin-A, and inhibin-A might play a role in C. trachomatis-infected tubal EP.
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Affiliation(s)
- Shipra Pant
- Molecular Microbiology Laboratory, ICMR-National Institute of Pathology, Sriramachari Bhawan, Safdarjung Hospital Campus, Post Box 4909, New Delhi 110029, India
| | - Tanu Bhati
- Molecular Microbiology Laboratory, ICMR-National Institute of Pathology, Sriramachari Bhawan, Safdarjung Hospital Campus, Post Box 4909, New Delhi 110029, India
| | - Astha Dimri
- Molecular Microbiology Laboratory, ICMR-National Institute of Pathology, Sriramachari Bhawan, Safdarjung Hospital Campus, Post Box 4909, New Delhi 110029, India
| | - Renu Arora
- Department of Obstetrics and Gynaecology, Vardhman Mahavir Medical College (VMMC) and Safdarjung Hospital, New Delhi 110029, India
| | - Fouzia Siraj
- Pathology Laboratory, ICMR-National Institute of Pathology, Sriramachari Bhawan, Safdarjung Hospital Campus, Post Box 4909, New Delhi 110029, India
| | - Sheikh Raisuddin
- Department of Medical Elementology and Toxicology, Jamia Hamdard, Hamdard Nagar, New Delhi 10062, India
| | - Sangita Rastogi
- Molecular Microbiology Laboratory, ICMR-National Institute of Pathology, Sriramachari Bhawan, Safdarjung Hospital Campus, Post Box 4909, New Delhi 110029, India
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13
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Ludwig EK, Hobbs KJ, McKinney-Aguirre CA, Gonzalez LM. Biomarkers of Intestinal Injury in Colic. Animals (Basel) 2023; 13:227. [PMID: 36670767 PMCID: PMC9854801 DOI: 10.3390/ani13020227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/03/2023] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
Biomarkers are typically proteins, enzymes, or other molecular changes that are elevated or decreased in body fluids during the course of inflammation or disease. Biomarkers pose an extremely attractive tool for establishing diagnoses and prognoses of equine gastrointestinal colic, one of the most prevalent causes of morbidity and mortality in horses. This topic has received increasing attention because early diagnosis of some forms of severe colic, such as intestinal ischemia, would create opportunities for rapid interventions that would likely improve case outcomes. This review explores biomarkers currently used in equine medicine for colic, including acute phase proteins, proinflammatory cytokines, markers of endotoxemia, and tissue injury metabolites. To date, no single biomarker has been identified that is perfectly sensitive and specific for intestinal ischemia; however, L-lactate has been proven to be a very functional and highly utilized diagnostic tool. However, further exploration of other biomarkers discussed in this review may provide the key to accelerated identification, intervention, and better outcomes for horses suffering from severe colic.
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Affiliation(s)
| | | | | | - Liara M. Gonzalez
- Department of Clinical Sciences, North Carolina State University, Raleigh, NC 27606, USA
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14
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Tsogtgerel M, Murase H, Moriyama H, Sato F, Nambo Y. Plasma activin A concentrations during late gestation in Thoroughbred mares with abnormal pregnancies. J Equine Vet Sci 2023; 120:104184. [PMID: 36470514 DOI: 10.1016/j.jevs.2022.104184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 11/22/2022] [Accepted: 11/29/2022] [Indexed: 12/04/2022]
Abstract
Late-term fetal loss in horses is a major problem in the horse-breeding industry globally. Abnormal pregnancies should be diagnosed as early as possible to prevent abortions and other gestational problems. According to our previous longitudinal study in healthy pregnant mares, the plasma activin A concentration increases as pregnancy progresses. The aim of the present study was to compare plasma activin A concentrations in healthy pregnant Thoroughbred mares (n=40) with those in pregnant mares that suffered fetal loss or showed abnormal symptoms (n=30) during late gestation. This field study found that plasma activin A concentrations were higher in the abnormal group (pregnancy loss, red bag delivery, premature udder development, and vaginal discharge) than the normal group (P < 0.001; cutoff value: ≥ 138.2 pg/mL; sensitivity, 74.4%; specificity, 77.5%). More specifically, plasma activin A concentrations in the "symptom" and "abnormal delivery" subgroups were higher than those in gestational-age-matched normal groups (P < 0.001). Nevertheless, the plasma activin A concentration in the "normal delivery" subgroup was not different from that in the "abnormal delivery" subgroup in samples collected within 10 days before delivery. In conclusion, this study is the first to demonstrate a significantly earlier increase in plasma activin A concentration in abnormal pregnancies of Thoroughbred mares during late gestation.
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Affiliation(s)
- Munkhtuul Tsogtgerel
- Department of Clinical Veterinary Sciences, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido, 080-8555, Japan; School of Veterinary Medicine, Mongolian University of Life Sciences, Ulaanbaatar, 17024, Mongolia
| | - Harutaka Murase
- Equine Science Division, Hidaka Training and Research Center, Japan Racing Association, Hokkaido, 057-0171, Japan
| | | | - Fumio Sato
- Equine Research Institute, Japan Racing Association, Tochigi, 329-0412, Japan
| | - Yasuo Nambo
- Department of Clinical Veterinary Sciences, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido, 080-8555, Japan.
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15
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Wang F, Zhang J, Wang Y, Chen Y, Han D. Viral tropism for the testis and sexual transmission. Front Immunol 2022; 13:1040172. [PMID: 36439102 PMCID: PMC9682072 DOI: 10.3389/fimmu.2022.1040172] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 10/24/2022] [Indexed: 10/17/2023] Open
Abstract
The mammalian testis adopts an immune privileged environment to protect male germ cells from adverse autoimmune reaction. The testicular immune privileged status can be also hijacked by various microbial pathogens as a sanctuary to escape systemic immune surveillance. In particular, several viruses have a tropism for the testis. To overcome the immune privileged status and mount an effective local defense against invading viruses, testicular cells are well equipped with innate antiviral machinery. However, several viruses may persist an elongated duration in the testis and disrupt the local immune homeostasis, thereby impairing testicular functions and male fertility. Moreover, the viruses in the testis, as well as other organs of the male reproductive system, can shed to the semen, thus allowing sexual transmission to partners. Viral infection in the testis, which can impair male fertility and lead to sexual transmission, is a serious concern in research on known and on new emerging viruses. To provide references for our scientific peers, this article reviews research achievements and suggests future research focuses in the field.
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Affiliation(s)
| | | | | | - Yongmei Chen
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Daishu Han
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
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16
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Dean B, Thomas EHX, Bozaoglu K, Tan EJ, Van Rheenen TE, Neill E, Sumner PJ, Carruthers SP, Scarr E, Rossell SL, Gurvich C. Evidence that a working memory cognitive phenotype within schizophrenia has a unique underlying biology. Psychiatry Res 2022; 317:114873. [PMID: 36252418 DOI: 10.1016/j.psychres.2022.114873] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 09/27/2022] [Accepted: 09/30/2022] [Indexed: 01/05/2023]
Abstract
It is suggested studying phenotypes within the syndrome of schizophrenia will accelerate understanding the complex molecular pathology of the disorder. Supporting this hypothesis, we have identified a sub-group within schizophrenia with impaired working memory (WM) and have used Affymetrix™ Human Exon 1.0 ST Arrays to compare their blood RNA levels (n=16) to a group of with intact WM (n=18). Levels of 72 RNAs were higher in blood from patients with impaired WM, 11 of which have proven links to the maintenance of different aspects of working memory (cognition). Overall, changed gene expression in those with impaired WM could be linked to cognition through glutamatergic activity, olfaction, immunity, inflammation as well as energy and metabolism. Our data gives preliminary support to the hypotheses that there is a working memory deficit phenotype within the syndrome of schizophrenia with has a biological underpinning. In addition, our data raises the possibility that a larger study could show that the specific changes in gene expression we have identified could prove to be the biomarkers needed to develop a blood test to identify those with impaired WM; a significant step toward allowing the use of personalised medicine directed toward improving their impaired working memory.
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Affiliation(s)
- Brian Dean
- The Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, Victoria, Australia.
| | - Elizabeth H X Thomas
- Monash Alfred Psychiatry Research Centre, Central Clinical School, Monash University and The Alfred Hospital, Melbourne, Victoria, Australia
| | - Kiymet Bozaoglu
- The Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Victoria, Australia
| | - Eric J Tan
- Centre for Mental Health, Swinburne University of Technology, Hawthorne, Victoria, Australia; Department of Psychiatry, St Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Tamsyn E Van Rheenen
- Centre for Mental Health, Swinburne University of Technology, Hawthorne, Victoria, Australia; Melbourne Neuropsychiatry Centre, University of Melbourne, Parkville, Victoria, Australia
| | - Erica Neill
- Centre for Mental Health, Swinburne University of Technology, Hawthorne, Victoria, Australia; Department of Psychiatry, St Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Philip J Sumner
- Centre for Mental Health, Swinburne University of Technology, Hawthorne, Victoria, Australia
| | - Sean P Carruthers
- Centre for Mental Health, Swinburne University of Technology, Hawthorne, Victoria, Australia
| | - Elizabeth Scarr
- Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Susan L Rossell
- Centre for Mental Health, Swinburne University of Technology, Hawthorne, Victoria, Australia; Department of Psychiatry, St Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Caroline Gurvich
- Monash Alfred Psychiatry Research Centre, Central Clinical School, Monash University and The Alfred Hospital, Melbourne, Victoria, Australia
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17
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Maekawa H, Jin Y, Nishio M, Kawai S, Nagata S, Kamakura T, Yoshitomi H, Niwa A, Saito MK, Matsuda S, Toguchida J. Recapitulation of pro-inflammatory signature of monocytes with ACVR1A mutation using FOP patient-derived iPSCs. Orphanet J Rare Dis 2022; 17:364. [PMID: 36131296 PMCID: PMC9494870 DOI: 10.1186/s13023-022-02506-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 09/04/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive heterotopic ossification (HO) in soft tissues due to a heterozygous mutation of the ACVR1A gene (FOP-ACVR1A), which erroneously transduces the BMP signal by Activin-A. Although inflammation is known to trigger HO in FOP, the role of FOP-ACVR1A on inflammatory cells remains to be elucidated. RESULTS We generated immortalized monocytic cell lines from FOP-iPSCs (FOP-ML) and mutation rescued iPSCs (resFOP-ML). Cell morphology was evaluated during the monocyte induction and after immortalization. Fluorescence-activated cell sorting (FACS) was performed to evaluate the cell surface markers CD14 and CD16 on MLs. MLs were stimulated with lipopolysaccharide or Activin-A and the gene expression was evaluated by quantitative PCR and microarray analysis. Histological analysis was performed for HO tissue obtained from wild type mice and FOP-ACVR1A mice which conditionally express human mutant ACVR1A gene by doxycycline administration. Without any stimulation, FOP-ML showed the pro-inflammatory signature of CD16+ monocytes with an upregulation of INHBA gene, and treatment of resFOP-ML with Activin-A induced an expression profile mimicking that of FOP-ML at baseline. Treatment of FOP-ML with Activin-A further induced the inflammatory profile with an up-regulation of inflammation-associated genes, of which some, but not all, of which were suppressed by corticosteroid. Experiments using an inhibitor for TGFβ or BMP signal demonstrated that Activin-A-induced genes such as CD16 and CCL7, were regulated by both signals, indicating Activin-A transduced dual signals in FOP-ML. A comparison with resFOP-ML identified several down-regulated genes in FOP-ML including LYVE-1, which is known to suppress matrix-formation in vivo. The down-regulation of LYVE-1 in HO tissues was confirmed in FOP model mice, verifying the significance of the in vitro experiments. CONCLUSION These results indicate that FOP-ML faithfully recapitulated the phenotype of primary monocytes of FOP and the combination with resFOP-ML is a useful tool to investigate molecular events at the initial inflammation stage of HO in FOP.
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Affiliation(s)
- Hirotsugu Maekawa
- Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.,Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yonghui Jin
- Department of Regeneration Sciences and Engineering, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Megumi Nishio
- Department of Regeneration Sciences and Engineering, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Shunsuke Kawai
- Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.,Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Sanae Nagata
- Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Takeshi Kamakura
- Department of Regeneration Sciences and Engineering, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Hiroyuki Yoshitomi
- Department of Regeneration Sciences and Engineering, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.,Department of Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Akira Niwa
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Megumu K Saito
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Shuichi Matsuda
- Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Junya Toguchida
- Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan. .,Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. .,Department of Regeneration Sciences and Engineering, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan. .,Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
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18
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Zhong X, Narasimhan A, Silverman LM, Young AR, Shahda S, Liu S, Wan J, Liu Y, Koniaris LG, Zimmers TA. Sex specificity of pancreatic cancer cachexia phenotypes, mechanisms, and treatment in mice and humans: role of Activin. J Cachexia Sarcopenia Muscle 2022; 13:2146-2161. [PMID: 35510530 PMCID: PMC9397557 DOI: 10.1002/jcsm.12998] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 02/04/2022] [Accepted: 03/16/2022] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Cachexia is frequent, deadly, and untreatable for patients with pancreatic ductal adenocarcinoma (PDAC). The reproductive hormone and cytokine Activin is a mediator of PDAC cachexia, and Activin receptor targeting was clinically tested for cancer cachexia therapy. However, sex-specific manifestations and mechanisms are poorly understood, constraining development of effective treatments. METHODS Cachexia phenotypes, muscle gene/protein expression, and effects of the Activin blocker ACVR2B/Fc were assessed in LSL-KrasG12D/+ , LSL-Trp53R172H/+ , and Pdx-1-Cre (KPC) mice with autochthonic PDAC. Effects of PDAC and sex hormones were modelled by treating C2C12 myotubes with KPC-cell conditioned medium (CM) and estradiol. Muscle gene expression by RNAseq and change in muscle from serial CT scans were measured in patients with PDAC. RESULTS Despite equivalent tumour latency (median 17 weeks) and mortality (24.5 weeks), male KPC mice showed earlier and more severe cachexia than females. In early PDAC, male gastrocnemius, quadriceps, and tibialis anterior muscles were reduced (-21.7%, -18.9%, and -20.8%, respectively, all P < 0.001), with only gastrocnemius reduced in females (-16%, P < 0.01). Sex differences disappeared in late PDAC. Plasma Activin A was similarly elevated between sexes throughout, while oestrogen and testosterone levels suggested a virilizing effect of PDAC in females. Estradiol partially protected myotubes from KPC-CM induced atrophy and promoted expression of the potential Activin inhibitor Fstl1. Early-stage female mice showed greater muscle expression of Activin inhibitors Fst, Fstl1, and Fstl3; this sex difference disappeared by late-stage PDAC. ACVR2B/Fc initiated in early PDAC preserved muscle and fat only in male KPC mice, with increases of 41.2%, 52.6%, 39.3%, and 348.8%, respectively, in gastrocnemius, quadriceps, tibialis, and fat pad weights vs. vehicle controls, without effect on tumour. No protection was observed in females. At protein and RNA levels, pro-atrophy pathways were induced more strongly in early-stage males, with sex differences less evident in late-stage disease. As with mass, ACVR2B/Fc blunted atrophy-associated pathways only in males. In patients with resectable PDAC, muscle expression of Activin inhibitors FSTL1, FSLT3, and WFIKKN2/GASP2 were higher in women than men. Overall, among 124 patients on first-line gemcitabine/nab-paclitaxel for PDAC, only men displayed muscle loss (P < 0.001); average muscle wasting in men was greater (-6.63 ± 10.70% vs. -1.62 ± 12.00% mean ± SD, P = 0.038) and more rapid (-0.0098 ± 0.0742%/day vs. -0.0466 ± 0.1066%/day, P = 0.017) than in women. CONCLUSIONS Pancreatic ductal adenocarcinoma cachexia displays sex-specific phenotypes in mice and humans, with Activin a preferential driver of muscle wasting in males. Sex is a major modulator of cachexia mechanisms. Consideration of sexual dimorphism is essential for discovery and development of effective treatments.
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Affiliation(s)
- Xiaoling Zhong
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
- Richard L. Roudebush Veterans Administration Medical CenterIndianapolisINUSA
| | - Ashok Narasimhan
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
| | | | - Andrew R. Young
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
| | - Safi Shahda
- Department of MedicineIndiana University School of MedicineIndianapolisINUSA
| | - Sheng Liu
- Department of Medical and Molecular GeneticsIndiana University School of MedicineIndianapolisINUSA
- Center for Computational Biology and BioinformaticsIndianapolisINUSA
| | - Jun Wan
- Department of Medical and Molecular GeneticsIndiana University School of MedicineIndianapolisINUSA
- Center for Computational Biology and BioinformaticsIndianapolisINUSA
- Indiana University Melvin and Bren Simon Comprehensive Cancer CenterIndianapolisINUSA
| | - Yunlong Liu
- Department of Medical and Molecular GeneticsIndiana University School of MedicineIndianapolisINUSA
- Center for Computational Biology and BioinformaticsIndianapolisINUSA
- Indiana University Melvin and Bren Simon Comprehensive Cancer CenterIndianapolisINUSA
- Indiana Center for Musculoskeletal HealthIndianapolisINUSA
| | - Leonidas G. Koniaris
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
- Richard L. Roudebush Veterans Administration Medical CenterIndianapolisINUSA
- Indiana University Melvin and Bren Simon Comprehensive Cancer CenterIndianapolisINUSA
- Indiana Center for Musculoskeletal HealthIndianapolisINUSA
| | - Teresa A. Zimmers
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
- Richard L. Roudebush Veterans Administration Medical CenterIndianapolisINUSA
- Center for Computational Biology and BioinformaticsIndianapolisINUSA
- Indiana University Melvin and Bren Simon Comprehensive Cancer CenterIndianapolisINUSA
- Indiana Center for Musculoskeletal HealthIndianapolisINUSA
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19
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Ling H, Luo L, Dai X, Chen H. Fallopian tubal infertility: the result of Chlamydia trachomatis-induced fallopian tubal fibrosis. Mol Cell Biochem 2021; 477:205-212. [PMID: 34652537 DOI: 10.1007/s11010-021-04270-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 09/29/2021] [Indexed: 11/26/2022]
Abstract
Chlamydia trachomatis is one of the most common pathogens of sexually transmitted diseases, and its incidence in genital tract infections is now 4.7% in south China. Infertility is the end result of C. trachomatis-induced fallopian tubal fibrosis and is receiving intense attention from scientists worldwide. To reduce the incidence of infertility, it is important to understand the pathology-related changes of the genital tract where C. trachomatis infection is significant, especially the mechanism of fibrosis formation. During fibrosis development, the fallopian tube becomes sticky and occluded, which will eventually lead to tubal infertility. At present, the mechanism of fallopian tubal fibrosis induced by C. trachomatis infection is unclear. Our study attempted to summarize the possible mechanisms of fibrosis caused by C. trachomatis infection in the fallopian tube by reviewing published studies and further providing potential therapeutic targets to reduce the occurrence of infertility. This study also provides ideas for future research. Factors leading to fallopian tube fibrosis include inflammatory factors, miRNA, ECT, cHSP, and host factors. We hypothesized that C. trachomatis mediates the transcription and translation of EMT and ECM via upregulating TGF signaling pathway, which leads to the formation of fallopian tube fibrosis and ultimately to tubal infertility.
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Affiliation(s)
- Hua Ling
- The First People's Hospital of Chenzhou, The First School of Clinical Medicine, Southern Medical University, Chenzhou, 423000, People's Republic of China
| | - Lipei Luo
- The First People's Hospital of Chenzhou, The First School of Clinical Medicine, Southern Medical University, Chenzhou, 423000, People's Republic of China
| | - Xingui Dai
- The First People's Hospital of Chenzhou, The First School of Clinical Medicine, Southern Medical University, Chenzhou, 423000, People's Republic of China.
- The First People's Hospital of Chenzhou, Chenzhou, 423000, People's Republic of China.
- The First Affiliated Hospital of Xiangnan University, Chenzhou, 423000, People's Republic of China.
| | - Hongliang Chen
- The First People's Hospital of Chenzhou, The First School of Clinical Medicine, Southern Medical University, Chenzhou, 423000, People's Republic of China.
- The First People's Hospital of Chenzhou, Chenzhou, 423000, People's Republic of China.
- The First Affiliated Hospital of Xiangnan University, Chenzhou, 423000, People's Republic of China.
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20
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Dutta S, Sandhu N, Sengupta P, Alves MG, Henkel R, Agarwal A. Somatic-Immune Cells Crosstalk In-The-Making of Testicular Immune Privilege. Reprod Sci 2021; 29:2707-2718. [PMID: 34580844 DOI: 10.1007/s43032-021-00721-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/22/2021] [Indexed: 11/27/2022]
Abstract
Immunological infertility contributes significantly to the etiology of idiopathic male infertility. Shielding the spermatogenic cells from systemic immune responses is fundamental to secure normal production of spermatozoa. The body's immune system is tuned with the host self-components since the early postnatal period, while sperm first develops during puberty, thus rendering spermatogenic proteins as 'non-self' or 'antigenic.' Development of antibodies to these antigens elicits autoimmune responses affecting sperm motility, functions, and fertility. Therefore, the testes need to establish a specialized immune-privileged microenvironment to protect the allogenic germ cells by orchestration of various testicular cells and resident immune cells. This is achieved through sequestration of antigenic germ cells by blood-testis barrier and actions of various endocrine, paracrine, immune-suppressive, and immunomodulatory mechanisms. The various mechanisms are very complex and need conceptual integration to disclose the exact physiological scenario, and to facilitate detection and management of immunogenic infertility caused by disruption of testicular immune regulation. The present review aims to (a) discuss the components of testicular immune privilege; (b) explain testicular somatic and immune cell interactions in establishing and maintaining the testicular immune micro-environment; and (c) illustrate the integration of multiple mechanisms involved in the control of immune privilege of the testis.
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Affiliation(s)
- Sulagna Dutta
- Department of Oral Biology and Biomedical Sciences, Faculty of Dentistry, MAHSA University, Jenjarom, Selangor , Malaysia
| | - Narpal Sandhu
- Molecular and Cellular Biology, University of California, Berkeley, CA, USA
| | - Pallav Sengupta
- Department of Physiology, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarom, Selangor , Malaysia
| | - Marco G Alves
- Department of Anatomy and Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Ralf Henkel
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Department of Medical Bioscience, University of the Western Cape, Bellville, South Africa
- LogixX Pharma, Theale, Berkshire, UK
| | - Ashok Agarwal
- American Center for Reproductive Medicine, Cleveland Clinic, Mail Code X-11, 10681 Carnegie Avenue, Cleveland, OH, 44195, USA.
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21
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Park G, Qian W, Zhang MJ, Chen YH, Ma LW, Zeng N, Lu Q, Li YY, Ma WW, Yin XF, Zhou BR, Luo D. Platelet-rich plasma regulating the repair of ultraviolet B-induced acute tissue inflammation: adjusting macrophage polarization through the activin receptor-follistatin system. Bioengineered 2021; 12:3125-3136. [PMID: 34193023 PMCID: PMC8806634 DOI: 10.1080/21655979.2021.1944026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Ultraviolet B (UVB) is one of the most common exogenous factors in skin aging, especially photoaging. Once a large amount of UVB accumulates within a short period of time, skin tissue can become inflamed. It has also been found in clinics that platelet-rich plasma (PRP) can promote wound repair; therefore, the aim of this study was to identify the mechanism by which PRP repairs UVB-induced skin photodamage. We used PRP of Sprague-Dawley rats with the two-spin technique in the established acute UVB radiation photodamage model and harvested the corresponding skin after 1, 7, and 28 d. Hematoxylin and eosin staining was used to observe tissue inflammation. We found that PRP reduces inflammation in the early stages of UVB-induced acute skin damage, and then promotes the proliferation of collagen in the middle and late stages. Moreover, PRP can stimulate Act A and M1 polarization in the early stage, while inhibiting activin A (Act A) and inducing M2 polarization in the middle and late stages. In conclusion, this study demonstrates that PRP plays an important regulatory role in helping reduce UVB-induced acute skin tissue inflammation by adjusting macrophage polarization, which alleviates skin inflammation and stimulates collagen regeneration.
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Affiliation(s)
- Gajin Park
- Department of Dermatology, the First Affiliated of Nanjing Medical University, Nanjing, China
| | - Wen Qian
- Department of Dermatology, the First Affiliated of Nanjing Medical University, Nanjing, China
| | - Mei-Jie Zhang
- Department of Dermatology, the First Affiliated of Nanjing Medical University, Nanjing, China
| | - Yi-He Chen
- Department of Dermatology, the First Affiliated of Nanjing Medical University, Nanjing, China
| | - Li-Wen Ma
- Department of Dermatology, the First Affiliated of Nanjing Medical University, Nanjing, China
| | - Ni Zeng
- Department of Dermatology, the First Affiliated of Nanjing Medical University, Nanjing, China
| | - Qian Lu
- Department of Dermatology, the First Affiliated of Nanjing Medical University, Nanjing, China
| | - Yue-Yue Li
- Department of Dermatology, the First Affiliated of Nanjing Medical University, Nanjing, China
| | - Wei-Wei Ma
- Department of Dermatology, the First Affiliated of Nanjing Medical University, Nanjing, China
| | - Xu-Feng Yin
- Department of Dermatology, the First Affiliated of Nanjing Medical University, Nanjing, China
| | - Bing-Rong Zhou
- Department of Dermatology, the First Affiliated of Nanjing Medical University, Nanjing, China
| | - Dan Luo
- Department of Dermatology, the First Affiliated of Nanjing Medical University, Nanjing, China
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Bmp8a is an essential positive regulator of antiviral immunity in zebrafish. Commun Biol 2021; 4:318. [PMID: 33750893 PMCID: PMC7943762 DOI: 10.1038/s42003-021-01811-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 02/05/2021] [Indexed: 02/06/2023] Open
Abstract
Bone morphogenetic protein (BMP) is a kind of classical multi-functional growth factor that plays a vital role in the formation and maintenance of bone, cartilage, muscle, blood vessels, and the regulation of adipogenesis and thermogenesis. However, understanding of the role of BMPs in antiviral immunity is still limited. Here we demonstrate that Bmp8a is a newly-identified positive regulator for antiviral immune responses. The bmp8a−/− zebrafish, when infected with viruses, show reduced antiviral immunity and increased viral load and mortality. We also show for the first time that Bmp8a interacts with Alk6a, which promotes the phosphorylation of Tbk1 and Irf3 through p38 MAPK pathway, and induces the production of type I interferons (IFNs) in response to viral infection. Our study uncovers a previously unrecognized role of Bmp8a in regulation of antiviral immune responses and provides a target for controlling viral infection. Zhang, Liu and colleagues identify the role of Bmp8a in antiviral immunity in zebrafish and provide mechanistic insight into its function. Bmp8a could serve as a future target for investigative studies of antiviral immune responses.
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Lin Y, Chen M, Zhang S, Feng Z, Wang J. Influence on proliferation and apoptosis of intestinal epithelial cells and expression of ACVR1 by Helicobacter pylori. EUR J INFLAMM 2021. [DOI: 10.1177/2058739220987108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
To discuss the influence on proliferation and apoptosis of human intestinal epithelial cells by Helicobacter pylori (Hp). CCK-8 method and flow cytometry to test the influence on proliferation and apoptosis of intestinal epithelial cells by Hp and cell cycle distribution. Immunocytochemistry, qRT-PCR, and WB to analyze the expression and activation of ACVR1. Functional studies of TNBS-induced IBD on mice and DSS-induced IBD on C57BL/6J mice with HP used for intervention were also performed. Hp facilitated the proliferation of intestinal epithelial cells with the breeding ratios on the first and third day are 5.24% ± 3.26% and 34.18% ± 6.68% respectively. ACVR1 is activated and the expression of anti-apoptosis protein Bcl-2 and Bcl-XL is up-regulated. In vivo, TNBS-induced and Hp-induced exhibited inflammatory lesions of intestine, ACVR1 and Bcl-2 higher expressions as compared to wild-type mice. Hp is likely to play a very important role in the proliferation, apoptosis, and malignant transformation of intestinal epithelial cells through ACVR1 pathway.
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Affiliation(s)
- Yunfeng Lin
- Department of Pediatrics, The Seventh Medical Center of PLA General Hospital, The Second School of Clinical Medicine, Southern Medical University, Beijing, China
- Department of Neonatology, Fujian Maternity and Children’s Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, China
- National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China
- Beijing Key Laboratory of Pediatric Organ Failure, Beijing, China
| | - Min Chen
- Department of Laboratory Medicine, Medical Technology and Engineering College, Fujian Medical University, Fuzhou, China
| | - Shuyu Zhang
- Department of Laboratory Medicine, Medical Technology and Engineering College, Fujian Medical University, Fuzhou, China
| | - Zhichun Feng
- Department of Pediatrics, The Seventh Medical Center of PLA General Hospital, The Second School of Clinical Medicine, Southern Medical University, Beijing, China
- National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China
- Beijing Key Laboratory of Pediatric Organ Failure, Beijing, China
| | - Jingwen Wang
- Department of Pathology, 1st Affiliated Hospital, Fujian Medical University, Fuzhou, China
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24
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Wu B, Zhang S, Guo Z, Bi Y, Zhou M, Li P, Seyedsadr M, Xu X, Li JL, Markovic-Plese S, Wan YY. The TGF-β superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation. Immunity 2021; 54:308-323.e6. [PMID: 33421362 DOI: 10.1016/j.immuni.2020.12.010] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 10/12/2020] [Accepted: 12/16/2020] [Indexed: 01/02/2023]
Abstract
Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor β1 (TGF-β1) is instrumental for Th17 cell differentiation, it is dispensable for generation of pathogenic Th17 cells. Here, we examined the T cell-intrinsic role of Activin-A, a TGF-β superfamily member closely related to TGF-β1, in pathogenic Th17 cell differentiation. Activin-A expression was increased in individuals with relapsing-remitting multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. Stimulation with interleukin-6 and Activin-A induced a molecular program that mirrored that of pathogenic Th17 cells and was inhibited by blocking Activin-A signaling. Genetic disruption of Activin-A and its receptor ALK4 in T cells impaired pathogenic Th17 cell differentiation in vitro and in vivo. Mechanistically, extracellular-signal-regulated kinase (ERK) phosphorylation, which was essential for pathogenic Th17 cell differentiation, was suppressed by TGF-β1-ALK5 but not Activin-A-ALK4 signaling. Thus, Activin-A drives pathogenic Th17 cell differentiation, implicating the Activin-A-ALK4-ERK axis as a therapeutic target for Th17 cell-related diseases.
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Affiliation(s)
- Bing Wu
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Song Zhang
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Zengli Guo
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yanmin Bi
- Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Mingxia Zhou
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ping Li
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | | | - Xiaojiang Xu
- Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - Jian-Liang Li
- Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - Silva Markovic-Plese
- Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Yisong Y Wan
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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25
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Martinez-Hackert E, Sundan A, Holien T. Receptor binding competition: A paradigm for regulating TGF-β family action. Cytokine Growth Factor Rev 2020; 57:39-54. [PMID: 33087301 DOI: 10.1016/j.cytogfr.2020.09.003] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 09/23/2020] [Indexed: 02/06/2023]
Abstract
The transforming growth factor (TGF)-β family is a group of structurally related, multifunctional growth factors, or ligands that are crucially involved in the development, regulation, and maintenance of animal tissues. In humans, the family counts over 33 members. These secreted ligands typically form multimeric complexes with two type I and two type II receptors to activate one of two distinct signal transduction branches. A striking feature of the family is its promiscuity, i.e., many ligands bind the same receptors and compete with each other for binding to these receptors. Although several explanations for this feature have been considered, its functional significance has remained puzzling. However, several recent reports have promoted the idea that ligand-receptor binding promiscuity and competition are critical features of the TGF-β family that provide an essential regulating function. Namely, they allow a cell to read and process multi-ligand inputs. This capability may be necessary for producing subtle, distinctive, or adaptive responses and, possibly, for facilitating developmental plasticity. Here, we review the molecular basis for ligand competition, with emphasis on molecular structures and binding affinities. We give an overview of methods that were used to establish experimentally ligand competition. Finally, we discuss how the concept of ligand competition may be fundamentally tied to human physiology, disease, and therapy.
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Affiliation(s)
- Erik Martinez-Hackert
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA.
| | - Anders Sundan
- Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology, 7491, Trondheim, Norway; Centre of Molecular Inflammation Research (CEMIR), Norwegian University of Science and Technology, 7491, Trondheim, Norway
| | - Toril Holien
- Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology, 7491, Trondheim, Norway; Department of Hematology, St. Olav's University Hospital, 7030, Trondheim, Norway.
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26
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Ries A, Schelch K, Falch D, Pany L, Hoda MA, Grusch M. Activin A: an emerging target for improving cancer treatment? Expert Opin Ther Targets 2020; 24:985-996. [PMID: 32700590 DOI: 10.1080/14728222.2020.1799350] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Activin A is involved in the regulation of a surprisingly broad number of processes that are relevant for cancer development and treatment; it is implicated in cell autonomous functions and multiple regulatory functions in the tumor microenvironment. AREAS COVERED This article summarizes the current knowledge about activin A in cell growth and death, migration and metastasis, angiogenesis, stemness and drug resistance, regulation of antitumor immunity, and cancer cachexia. We explore the role of activin A as a biomarker and discuss strategies for using it as target for cancer therapy. Literature retrieved from Medline until 25 June 2020 was considered. EXPERT OPINION While many functions of activin A were investigated in preclinical models, there is currently limited experience from clinical trials. Activin A has growth- and migration-promoting effects, contributes to immune evasion and cachexia and is associated with shorter survival in several cancer types. Targeting activin A could offer the chance to simultaneously limit tumor growth and spreading, improve drug response, boost antitumor immune responses and improve cancer-associated or treatment-associated cachexia, bone loss, and anemia. Nevertheless, defining which patients have the highest likelihood of benefiting from these effects is challenging and will require further work.
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Affiliation(s)
- Alexander Ries
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna , Vienna, Austria
| | - Karin Schelch
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna , Vienna, Austria
| | - David Falch
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna , Vienna, Austria
| | - Laura Pany
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna , Vienna, Austria
| | - Mir Alireza Hoda
- Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna , Vienna, Austria
| | - Michael Grusch
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna , Vienna, Austria
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27
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Soler Palacios B, Nieto C, Fajardo P, González de la Aleja A, Andrés N, Dominguez-Soto Á, Lucas P, Cuenda A, Rodríguez-Frade JM, Martínez-A C, Villares R, Corbí ÁL, Mellado M. Growth Hormone Reprograms Macrophages toward an Anti-Inflammatory and Reparative Profile in an MAFB-Dependent Manner. THE JOURNAL OF IMMUNOLOGY 2020; 205:776-788. [PMID: 32591394 DOI: 10.4049/jimmunol.1901330] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 05/24/2020] [Indexed: 12/12/2022]
Abstract
Growth hormone (GH), a pleiotropic hormone secreted by the pituitary gland, regulates immune and inflammatory responses. In this study, we show that GH regulates the phenotypic and functional plasticity of macrophages both in vitro and in vivo. Specifically, GH treatment of GM-CSF-primed monocyte-derived macrophages promotes a significant enrichment of anti-inflammatory genes and dampens the proinflammatory cytokine profile through PI3K-mediated downregulation of activin A and upregulation of MAFB, a critical transcription factor for anti-inflammatory polarization of human macrophages. These in vitro data correlate with improved remission of inflammation and mucosal repair during recovery in the acute dextran sodium sulfate-induced colitis model in GH-overexpressing mice. In this model, in addition to the GH-mediated effects on other immune cells, we observed that macrophages from inflamed gut acquire an anti-inflammatory/reparative profile. Overall, these data indicate that GH reprograms inflammatory macrophages to an anti-inflammatory phenotype and improves resolution during pathologic inflammatory responses.
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Affiliation(s)
- Blanca Soler Palacios
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; and
| | - Concha Nieto
- Departamento de Biología Molecular y Celular, Centro de Investigaciones Biológicas/Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain
| | - Pilar Fajardo
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; and
| | - Arturo González de la Aleja
- Departamento de Biología Molecular y Celular, Centro de Investigaciones Biológicas/Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain
| | - Nuria Andrés
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; and
| | - Ángeles Dominguez-Soto
- Departamento de Biología Molecular y Celular, Centro de Investigaciones Biológicas/Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain
| | - Pilar Lucas
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; and
| | - Ana Cuenda
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; and
| | - José Miguel Rodríguez-Frade
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; and
| | - Carlos Martínez-A
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; and
| | - Ricardo Villares
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; and
| | - Ángel L Corbí
- Departamento de Biología Molecular y Celular, Centro de Investigaciones Biológicas/Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain
| | - Mario Mellado
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; and
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28
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Grandon B, Rincheval-Arnold A, Jah N, Corsi JM, Araujo LM, Glatigny S, Prevost E, Roche D, Chiocchia G, Guénal I, Gaumer S, Breban M. HLA-B27 alters BMP/TGFβ signalling in Drosophila, revealing putative pathogenic mechanism for spondyloarthritis. Ann Rheum Dis 2019; 78:1653-1662. [PMID: 31563893 DOI: 10.1136/annrheumdis-2019-215832] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 09/08/2019] [Accepted: 09/09/2019] [Indexed: 01/16/2023]
Abstract
OBJECTIVES The human leucocyte antigen (HLA)-B27 confers an increased risk of spondyloarthritis (SpA) by unknown mechanism. The objective of this work was to uncover HLA-B27 non-canonical properties that could explain its pathogenicity, using a new Drosophila model. METHODS We produced transgenic Drosophila expressing the SpA-associated HLA-B*27:04 or HLA-B*27:05 subtypes, or the non-associated HLA-B*07:02 allele, alone or in combination with human β2-microglobulin (hβ2m), under tissue-specific drivers. Consequences of transgenes expression in Drosophila were examined and affected pathways were investigated by the genetic interaction experiments. Predictions of the model were further tested in immune cells from patients with SpA. RESULTS Loss of crossveins in the wings and a reduced eye phenotype were observed after expression of HLA-B*27:04 or HLA-B*27:05 in Drosophila but not in fruit flies expressing the non-associated HLA-B*07:02 allele. These HLA-B27-induced phenotypes required the presence of hβ2m that allowed expression of well-folded HLA-B conformers at the cell surface. Loss of crossveins resulted from a dominant negative effect of HLA-B27 on the type I bone morphogenetic protein (BMP) receptor saxophone (Sax) with which it interacted, resulting in elevated mothers against decapentaplegic (Mad, a Drosophila receptor-mediated Smad) phosphorylation. Likewise, in immune cells from patients with SpA, HLA-B27 specifically interacted with activin receptor-like kinase-2 (ALK2), the mammalian Sax ortholog, at the cell surface and elevated Smad phosphorylation was observed in response to activin A and transforming growth factor β (TGFβ). CONCLUSIONS Antagonistic interaction of HLA-B27 with ALK2, which exerts inhibitory functions on the TGFβ/BMP signalling pathway at the cross-road between inflammation and ossification, could adequately explain SpA development.
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Affiliation(s)
- Benjamin Grandon
- LGBC, EA4589, UVSQ/Université Paris-Saclay, EPHE/PSL Research University, Montigny-le-Bretonneux, France
- Infection & Inflammation, UMR 1173, Inserm, UVSQ/ Université Paris Saclay, Montigny-le-Bretonneux, France
| | - Aurore Rincheval-Arnold
- LGBC, EA4589, UVSQ/Université Paris-Saclay, EPHE/PSL Research University, Montigny-le-Bretonneux, France
| | - Nadège Jah
- Infection & Inflammation, UMR 1173, Inserm, UVSQ/ Université Paris Saclay, Montigny-le-Bretonneux, France
| | - Jean-Marc Corsi
- LGBC, EA4589, UVSQ/Université Paris-Saclay, EPHE/PSL Research University, Montigny-le-Bretonneux, France
| | - Luiza M Araujo
- Infection & Inflammation, UMR 1173, Inserm, UVSQ/ Université Paris Saclay, Montigny-le-Bretonneux, France
| | - Simon Glatigny
- Infection & Inflammation, UMR 1173, Inserm, UVSQ/ Université Paris Saclay, Montigny-le-Bretonneux, France
| | - Erwann Prevost
- LGBC, EA4589, UVSQ/Université Paris-Saclay, EPHE/PSL Research University, Montigny-le-Bretonneux, France
- Infection & Inflammation, UMR 1173, Inserm, UVSQ/ Université Paris Saclay, Montigny-le-Bretonneux, France
| | - Delphine Roche
- LGBC, EA4589, UVSQ/Université Paris-Saclay, EPHE/PSL Research University, Montigny-le-Bretonneux, France
| | - Gilles Chiocchia
- Infection & Inflammation, UMR 1173, Inserm, UVSQ/ Université Paris Saclay, Montigny-le-Bretonneux, France
| | - Isabelle Guénal
- LGBC, EA4589, UVSQ/Université Paris-Saclay, EPHE/PSL Research University, Montigny-le-Bretonneux, France
| | - Sébastien Gaumer
- LGBC, EA4589, UVSQ/Université Paris-Saclay, EPHE/PSL Research University, Montigny-le-Bretonneux, France
| | - Maxime Breban
- Infection & Inflammation, UMR 1173, Inserm, UVSQ/ Université Paris Saclay, Montigny-le-Bretonneux, France
- Rheumatology, Ambroise Paré Hospital, Boulogne Billancourt, France
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Follistatin and Soluble Endoglin Predict 1-Year Nonrelapse Mortality after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2019; 26:606-611. [PMID: 31715306 DOI: 10.1016/j.bbmt.2019.11.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 10/21/2019] [Accepted: 11/03/2019] [Indexed: 12/17/2022]
Abstract
Damage-associated angiogenic factors (AFs), including follistatin (FS) and soluble endoglin (sEng), are elevated in circulation at the onset of acute graft-versus-host disease (GVHD). We hypothesized that regimen-related tissue injury also might be associated with aberrant AF levels and sought to determine the relevance of these AF on nonrelapse mortality (NRM) in patients with acute GVHD and those without acute GVHD. To test our hypothesis, we analyzed circulating levels of FS, sEng, angiopoietin-2 (Ang2), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) A and B, placental growth factor (PlGF), and soluble VEGF receptor (sVEGFR)-1 and -2, in plasma samples from patients enrolled on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402 (n = 221), which tested GVHD prophylaxis after myeloablative hematopoietic stem cell transplantation (HCT). We found that the interaction between FS and sEng had an additive effect in their association with 1-year NRM. In multivariate analysis, patients with the highest levels of day +28 FS and sEng had a 14.9-fold greater hazard ratio (HR) of NRM (95% confidence interval, 3.2 to 69.4; P < .01) when compared with low levels of FS and sEng. We validated these findings using an external cohort of patients (n = 106). Pre-HCT measurements of FS and sEng were not associated with NRM, suggesting that elevations in these factors early post-HCT may be consequences of early regimen-related toxicity. Determining the mechanisms responsible for patient-specific vulnerability to treatment toxicities and endothelial damage associated with specific AF elevation may guide interventions to reduce NRM post-HCT.
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The role of Activin A in fibrodysplasia ossificans progressiva: a prominent mediator. Biosci Rep 2019; 39:BSR20190377. [PMID: 31341010 PMCID: PMC6680371 DOI: 10.1042/bsr20190377] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 07/16/2019] [Accepted: 07/23/2019] [Indexed: 12/31/2022] Open
Abstract
Heterotopic ossification (HO) is the aberrant formation of mature, lamellar bone in nonosseous tissue. Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disorder that causes progressive HO in the ligaments, tendons, and muscles throughout the body. FOP is attributed to an autosomal mutation in activin receptor-like kinase 2 (ALK2), a bone morphogenetic protein (BMP) type I receptor. Initial studies show that mutant ALK2 drives HO by constitutively activating the BMP signaling pathway. Recently, mutant ALK2 has been shown to transduce Smad1/5 signaling and enhance chondrogenesis, calcification in response to Activin A, which normally signals through Smad2/3 and inhibits BMP signaling pathway. Furthermore, Activin A induces heterotopic bone formation via mutant ALK2, while inhibition of Activin A blocks spontaneous and trauma-induced HO. In this manuscript, we describe the molecular mechanism of the causative gene ALK2 in FOP, mainly focusing on the prominent role of Activin A in HO. It reveals a potential strategy for prevention and treatment of FOP by inhibition of Activin A. Further studies are needed to explore the cellular and molecular mechanisms of Activin A in FOP in more detail.
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31
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Roudebush C, Catala-Valentin A, Andl T, Le Bras GF, Andl CD. Activin A-mediated epithelial de-differentiation contributes to injury repair in an in vitro gastrointestinal reflux model. Cytokine 2019; 123:154782. [PMID: 31369967 DOI: 10.1016/j.cyto.2019.154782] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 07/08/2019] [Accepted: 07/10/2019] [Indexed: 02/08/2023]
Abstract
Reflux esophagitis is a result of esophageal exposure to acid and bile during episodes of gastroesophageal reflux. Aside from chemical injury to the esophageal epithelium, it has been shown that acid and bile induce cytokine-mediated injury by stimulating the release of pro-inflammatory cytokines. During the repair and healing process following reflux injury, the squamous esophageal cells are replaced with a columnar epithelium causing Barrett's metaplasia, which predisposes patients to esophageal adenocarcinoma. We identified a novel player in gastroesophageal reflux injury, the TGFβ family member Activin A (ActA), which is a known regulator of inflammation and tissue repair. In this study, we show that in response to bile salt and acidified media (pH 4) exposure, emulating the milieu to which the distal esophagus is exposed during gastroesophageal reflux, long-term treated, tolerant esophageal keratinocytes exhibit increased ActA secretion and a pro-inflammatory cytokine signature. Furthermore, we noted increased motility and expression of the stem cell markers SOX9, LGR5 and DCLK1 supporting the notion that repair mechanisms were activated in the bile salt/acid-tolerant keratinocytes. Additionally, these experiments demonstrated that de-differentiation as characterized by the induction of YAP1, FOXO3 and KRT17 was altered by ActA/TGFβ signaling. Collectively, our results suggest a pivotal role for ActA in the inflammatory GERD environment by modulating esophageal tissue repair and de-differentiation.
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Affiliation(s)
- Cedric Roudebush
- Burnett School of Biomedical Sciences, University of Central Florida, 4110 Libra Dr., BMS, Building 20, rm 223, Orlando, FL 32816, United States
| | - Alma Catala-Valentin
- Burnett School of Biomedical Sciences, University of Central Florida, 4110 Libra Dr., BMS, Building 20, rm 223, Orlando, FL 32816, United States
| | - Thomas Andl
- Burnett School of Biomedical Sciences, University of Central Florida, 4110 Libra Dr., BMS, Building 20, rm 223, Orlando, FL 32816, United States
| | - Gregoire F Le Bras
- Burnett School of Biomedical Sciences, University of Central Florida, 4110 Libra Dr., BMS, Building 20, rm 223, Orlando, FL 32816, United States
| | - Claudia D Andl
- Burnett School of Biomedical Sciences, University of Central Florida, 4110 Libra Dr., BMS, Building 20, rm 223, Orlando, FL 32816, United States.
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Trachana V, Mourmoura E, Papathanasiou I, Tsezou A. Understanding the role of chondrocytes in osteoarthritis: utilizing proteomics. Expert Rev Proteomics 2019; 16:201-213. [DOI: 10.1080/14789450.2019.1571918] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Varvara Trachana
- Laboratory of Biology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Evanthia Mourmoura
- Laboratory of Cytogenetics and Molecular Genetics, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Ioanna Papathanasiou
- Laboratory of Cytogenetics and Molecular Genetics, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Aspasia Tsezou
- Laboratory of Biology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
- Laboratory of Cytogenetics and Molecular Genetics, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
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Abstract
Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor-β family of ligands. BMPs exhibit widespread utility and pleiotropic, context-dependent effects, and the strength and duration of BMP pathway signaling is tightly regulated at numerous levels via mechanisms operating both inside and outside the cell. Defects in the BMP pathway or its regulation underlie multiple human diseases of different organ systems. Yet much remains to be discovered about the BMP pathway in its original context, i.e., the skeleton. In this review, we provide a comprehensive overview of the intricacies of the BMP pathway and its inhibitors in bone development, homeostasis, and disease. We frame the content of the review around major unanswered questions for which incomplete evidence is available. First, we consider the gene regulatory network downstream of BMP signaling in osteoblastogenesis. Next, we examine why some BMP ligands are more osteogenic than others and what factors limit BMP signaling during osteoblastogenesis. Then we consider whether specific BMP pathway components are required for normal skeletal development, and if the pathway exerts endogenous effects in the aging skeleton. Finally, we propose two major areas of need of future study by the field: greater resolution of the gene regulatory network downstream of BMP signaling in the skeleton, and an expanded repertoire of reagents to reliably and specifically inhibit individual BMP pathway components.
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Affiliation(s)
- Jonathan W Lowery
- Division of Biomedical Science, Marian University College of Osteopathic Medicine , Indianapolis, Indiana ; and Department of Developmental Biology, Harvard School of Dental Medicine , Boston, Massachusetts
| | - Vicki Rosen
- Division of Biomedical Science, Marian University College of Osteopathic Medicine , Indianapolis, Indiana ; and Department of Developmental Biology, Harvard School of Dental Medicine , Boston, Massachusetts
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Bloise E, Ciarmela P, Dela Cruz C, Luisi S, Petraglia F, Reis FM. Activin A in Mammalian Physiology. Physiol Rev 2019; 99:739-780. [DOI: 10.1152/physrev.00002.2018] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be combined with alpha subunits to form inhibins. Activins were discovered in 1986 following the isolation of inhibins from porcine follicular fluid, and were characterized as ovarian hormones that stimulate follicle stimulating hormone (FSH) release by the pituitary gland. In particular, activin A was shown to be the isoform of greater physiological importance in humans. The current understanding of activin A surpasses the reproductive system and allows its classification as a hormone, a growth factor, and a cytokine. In more than 30 yr of intense research, activin A was localized in female and male reproductive organs but also in other organs and systems as diverse as the brain, liver, lung, bone, and gut. Moreover, its roles include embryonic differentiation, trophoblast invasion of the uterine wall in early pregnancy, and fetal/neonate brain protection in hypoxic conditions. It is now recognized that activin A overexpression may be either cytostatic or mitogenic, depending on the cell type, with important implications for tumor biology. Activin A also regulates bone formation and regeneration, enhances joint inflammation in rheumatoid arthritis, and triggers pathogenic mechanisms in the respiratory system. In this 30-yr review, we analyze the evidence for physiological roles of activin A and the potential use of activin agonists and antagonists as therapeutic agents.
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Affiliation(s)
- Enrrico Bloise
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Pasquapina Ciarmela
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Cynthia Dela Cruz
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Stefano Luisi
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Felice Petraglia
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Fernando M. Reis
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
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Peng LN, Chou MY, Liang CK, Lee WJ, Kojima T, Lin MH, Loh CH, Chen LK. Association between serum activin A and metabolic syndrome in older adults: Potential of activin A as a biomarker of cardiometabolic disease. Exp Gerontol 2018; 111:197-202. [PMID: 30071284 DOI: 10.1016/j.exger.2018.07.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 06/18/2018] [Accepted: 07/28/2018] [Indexed: 12/11/2022]
Abstract
Cardiovascular disease imposes substantial burdens of morbidity and mortality that increase with population aging. Estimating cardiometabolic risk accurately and expediently is challenging, and no single biomarker is satisfactory; hence, we investigated the potential of serum activin A for this purpose. Study data were collected from 433 community-dwelling adults age ≥53 years from Yilan County, Taiwan. Data included: demographics and medical history; physical measurements (blood pressure, body mass index, waist circumference); comprehensive functional assessments (frailty, cognitive function, depressive symptoms, nutritional status); fasting blood biochemistry (glucose, high-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, insulin-like growth factor-1, activin A, stratified into high, medium and low tertiles, and others); and dual-energy X-ray absorptiometry. Metabolic syndrome was considered a proxy for overall cardiometabolic risk. Subjects mean age was 69.3 ± 9.2 years, 48.3% were males. Compared to women, men had higher systolic blood pressure, education levels, relative appendicular skeletal muscle mass, waist circumference, physical activity, walking speed, free androgen index, and levels of serum uric acid, alanine aminotransferase, and dehydroepiandrosterone sulfate. High activin A was significantly associated with age, relative appendicular skeletal muscle mass in both gender, waist circumference in women, current alcohol drinking, hypertension, and Charlson Comorbidity Index. There were dose-dependent relationships (low to high) between serum activin A and frailty, cognitive impairment, malnutrition, metabolic syndrome, uric acid, and high-sensitivity C-reactive protein. Logistic regression analyses showed older age, serum uric acid, and metabolic syndrome were significantly associated with medium and high activin-A status, whereas, skeletal muscle mass, insulin-like growth factor-1 and dehydroepiandrosterone sulphate were associated with high, but not medium, serum activin A. This discovery of a dose-dependent association between serum activin A levels, age, and metabolic syndrome, suggests activin A may be a biomarker of overall cardiometabolic risk; however, further studies are needed to evaluate its potential applications in assessing and managing cardiometabolic risk.
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Affiliation(s)
- Li-Ning Peng
- Department of Geriatric Medicine, National Yang Ming University School of Medicine, 115, Sec. 2, Linong St., Taipei 11221, Taiwan; Aging and Health Research Center, National Yang Ming University, 155, Sec. 2, Linong St., Taipei 11221, Taiwan; Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, 201, Sec. 2, Shih-Pai Rd., Taipei 11217, Taiwan
| | - Ming-Yueh Chou
- Department of Geriatric Medicine, National Yang Ming University School of Medicine, 115, Sec. 2, Linong St., Taipei 11221, Taiwan; Aging and Health Research Center, National Yang Ming University, 155, Sec. 2, Linong St., Taipei 11221, Taiwan; Center for Geriatrics and Gerontology, Kaohsiung Veterans General Hospital, 386 Ta-Chun 1st Rd., Kaohsiung 81362, Taiwan
| | - Chih-Kuang Liang
- Department of Geriatric Medicine, National Yang Ming University School of Medicine, 115, Sec. 2, Linong St., Taipei 11221, Taiwan; Aging and Health Research Center, National Yang Ming University, 155, Sec. 2, Linong St., Taipei 11221, Taiwan; Center for Geriatrics and Gerontology, Kaohsiung Veterans General Hospital, 386 Ta-Chun 1st Rd., Kaohsiung 81362, Taiwan
| | - Wei-Ju Lee
- Department of Geriatric Medicine, National Yang Ming University School of Medicine, 115, Sec. 2, Linong St., Taipei 11221, Taiwan; Aging and Health Research Center, National Yang Ming University, 155, Sec. 2, Linong St., Taipei 11221, Taiwan; Department of Family Medicine, Taipei Veterans General Hospital Yuanshan Branch, 386 Rongguang Rd., Yuanshan Township, YiLan County 264, Taiwan
| | - Taro Kojima
- Department of Geriatric Medicine, Graduate Institute of Medicine, The University of Tokyo, 7-3-1 Jongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Ming-Hsien Lin
- Department of Geriatric Medicine, National Yang Ming University School of Medicine, 115, Sec. 2, Linong St., Taipei 11221, Taiwan; Aging and Health Research Center, National Yang Ming University, 155, Sec. 2, Linong St., Taipei 11221, Taiwan; Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, 201, Sec. 2, Shih-Pai Rd., Taipei 11217, Taiwan
| | - Ching-Hui Loh
- Department of Geriatric Medicine, National Yang Ming University School of Medicine, 115, Sec. 2, Linong St., Taipei 11221, Taiwan; Aging and Health Research Center, National Yang Ming University, 155, Sec. 2, Linong St., Taipei 11221, Taiwan; Center for Aging and Health, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 707, Sec. 3, Chung Yang Rd., Hualien 970, Taiwan
| | - Liang-Kung Chen
- Department of Geriatric Medicine, National Yang Ming University School of Medicine, 115, Sec. 2, Linong St., Taipei 11221, Taiwan; Aging and Health Research Center, National Yang Ming University, 155, Sec. 2, Linong St., Taipei 11221, Taiwan; Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, 201, Sec. 2, Shih-Pai Rd., Taipei 11217, Taiwan.
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Increased activin A levels in prediabetes and association with carotid intima-media thickness: a cross-sectional analysis from I-Lan Longitudinal Aging Study. Sci Rep 2018; 8:9957. [PMID: 29967428 PMCID: PMC6028626 DOI: 10.1038/s41598-018-27795-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 06/04/2018] [Indexed: 12/14/2022] Open
Abstract
Activin A and its binding protein follistatin may be crucial in glucose homeostasis, as multifunctional proteins mediating inflammatory and anti-inflammatory effects. However, clinical data on the activin A level in prediabetes, and the association between the circulating activin A level and carotid intima-media thickness (cIMT), are lacking. We aimed to investigate activin A and follistatin levels and their associations with cIMT. In total, 470 inhabitants of I-Lan county (235 men; mean age 69 ± 9 years) with measurements of serum activin A and follistatin levels were included. Patients with prediabetes and diabetes had significantly increased activin A concentrations compared with those in the normal glycemic group (both p < 0.001). A multivariable logistic regression model demonstrated that the circulating activin A level was associated with prediabetes and diabetes independently of other risk factors. Moreover, the circulating activin A levels were associated positively with cIMT in prediabetes (rs = 0.264, p = 0.001). In conclusion, activin A level, but not follistatin, was elevated independent of demographic variables with borderline significance and was correlated positively with cIMT in prediabetes. Activin A and follistatin levels were elevated in diabetes. In addition, elevated activin A was an independent risk factor for prediabetes and diabetes.
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James RG, Reeves SR, Barrow KA, White MP, Glukhova VA, Haghighi C, Seyoum D, Debley JS. Deficient Follistatin-like 3 Secretion by Asthmatic Airway Epithelium Impairs Fibroblast Regulation and Fibroblast-to-Myofibroblast Transition. Am J Respir Cell Mol Biol 2018; 59:104-113. [PMID: 29394092 PMCID: PMC6039878 DOI: 10.1165/rcmb.2017-0025oc] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 02/01/2018] [Indexed: 01/03/2023] Open
Abstract
Bronchial epithelial cells (BECs) from healthy children inhibit human lung fibroblast (HLF) expression of collagen and fibroblast-to-myofibroblast transition (FMT), whereas asthmatic BECs do so less effectively, suggesting that diminished epithelial-derived regulatory factors contribute to airway remodeling. Preliminary data demonstrated that secretion of the activin A inhibitor follistatin-like 3 (FSTL3) by healthy BECs was greater than that by asthmatic BECs. We sought to determine the relative secretion of FSTL3 and activin A by asthmatic and healthy BECs, and whether FSTL3 inhibits FMT. To quantify the abundance of the total proteome FSTL3 and activin A in supernatants of differentiated BEC cultures from healthy children and children with asthma, we performed mass spectrometry and ELISA. HLFs were cocultured with primary BECs and then HLF expression of collagen I and α-smooth muscle actin (α-SMA) was quantified by qPCR, and FMT was quantified by flow cytometry. Loss-of-function studies were conducted using lentivirus-delivered shRNA. Using mass spectrometry and ELISA results from larger cohorts, we found that FSTL3 concentrations were greater in media conditioned by healthy BECs compared with asthmatic BECs (4,012 vs. 2,553 pg/ml; P = 0.002), and in media conditioned by asthmatic BECs from children with normal lung function relative to those with airflow obstruction (FEV1/FVC ratio < 0.8; n = 9; 3,026 vs. 1,922 pg/ml; P = 0.04). shRNA depletion of FSTL3 in BECs (n = 8) increased HLF collagen I expression by 92% (P = 0.001) and α-SMA expression by 88% (P = 0.02), and increased FMT by flow cytometry in cocultured HLFs, whereas shRNA depletion of activin A (n = 6) resulted in decreased α-SMA (22%; P = 0.01) expression and decreased FMT. Together, these results indicate that deficient FSTL3 expression by asthmatic BECs impairs epithelial regulation of HLFs and FMT.
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Affiliation(s)
- Richard G. James
- Department of Pediatrics
- Department of Pharmacology, and
- Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, Washington
| | - Stephen R. Reeves
- Division of Pulmonary Medicine, Seattle Children’s Hospital, University of Washington, Seattle, Washington; and
- Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, Washington
| | - Kaitlyn A. Barrow
- Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, Washington
| | - Maria P. White
- Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, Washington
| | - Veronika A. Glukhova
- Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, Washington
| | - Candace Haghighi
- Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, Washington
| | - Dana Seyoum
- Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, Washington
| | - Jason S. Debley
- Division of Pulmonary Medicine, Seattle Children’s Hospital, University of Washington, Seattle, Washington; and
- Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, Washington
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Diesselberg C, Ribes S, Seele J, Kaufmann A, Redlich S, Bunkowski S, Hanisch UK, Michel U, Nau R, Schütze S. Activin A increases phagocytosis of Escherichia coli K1 by primary murine microglial cells activated by toll-like receptor agonists. J Neuroinflammation 2018; 15:175. [PMID: 29880000 PMCID: PMC5992782 DOI: 10.1186/s12974-018-1209-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 05/20/2018] [Indexed: 12/20/2022] Open
Abstract
Background Bacterial meningitis is associated with high mortality and long-term neurological sequelae. Increasing the phagocytic activity of microglia could improve the resistance of the CNS against infections. We studied the influence of activin A, a member of the TGF-β family with known immunoregulatory and neuroprotective effects, on the functions of microglial cells in vitro. Methods Primary murine microglial cells were treated with activin A (0.13 ng/ml–13 μg/ml) alone or in combination with agonists of TLR2, 4, and 9. Phagocytosis of Escherichia coli K1 as well as release of TNF-α, IL-6, CXCL1, and NO was assessed. Results Activin A dose-dependently enhanced the phagocytosis of Escherichia coli K1 by microglial cells activated by agonists of TLR2, 4, and 9 without further increasing NO and proinflammatory cytokine release. Cell viability of microglial cells was not affected by activin A. Conclusions Priming of microglial cells with activin A could increase the elimination of bacteria in bacterial CNS infections. This preventive strategy could improve the resistance of the brain to infections, particularly in elderly and immunocompromised patients.
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Affiliation(s)
- Catharina Diesselberg
- Institute of Neuropathology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany
| | - Sandra Ribes
- Institute of Neuropathology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany
| | - Jana Seele
- Institute of Neuropathology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.,Department of Geriatrics, Evangelisches Krankenhaus Göttingen-Weende, An der Lutter 24, 37075, Göttingen, Germany
| | - Annika Kaufmann
- Institute of Neuropathology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany
| | - Sandra Redlich
- Institute of Neuropathology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany
| | - Stephanie Bunkowski
- Institute of Neuropathology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany
| | - Uwe-Karsten Hanisch
- Institute of Neuropathology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany
| | - Uwe Michel
- Department of Neurology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany
| | - Roland Nau
- Institute of Neuropathology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.,Department of Geriatrics, Evangelisches Krankenhaus Göttingen-Weende, An der Lutter 24, 37075, Göttingen, Germany
| | - Sandra Schütze
- Institute of Neuropathology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany. .,Department of Geriatrics, AGAPLESION Frankfurter Diakonie Kliniken, Wilhelm-Epstein-Str. 4, 60431, Frankfurt am Main, Germany.
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Cappato S, Giacopelli F, Ravazzolo R, Bocciardi R. The Horizon of a Therapy for Rare Genetic Diseases: A "Druggable" Future for Fibrodysplasia Ossificans Progressiva. Int J Mol Sci 2018; 19:ijms19040989. [PMID: 29587443 PMCID: PMC5979309 DOI: 10.3390/ijms19040989] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Revised: 03/21/2018] [Accepted: 03/22/2018] [Indexed: 12/21/2022] Open
Abstract
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive extra-skeletal ossification leading to cumulative and severe disability. FOP has an extremely variable and episodic course and can be induced by trauma, infections, iatrogenic harms, immunization or can occur in an unpredictable way, without any recognizable trigger. The causative gene is ACVR1, encoding the Alk-2 type I receptor for bone morphogenetic proteins (BMPs). The signaling is initiated by BMP binding to a receptor complex consisting of type I and II molecules and can proceed into the cell through two main pathways, a canonical, SMAD-dependent signaling and a p38-mediated cascade. Most FOP patients carry the recurrent R206H substitution in the receptor Glycine-Serine rich (GS) domain, whereas a few other mutations are responsible for a limited number of cases. Mutations cause a dysregulation of the downstream BMP-dependent pathway and make mutated ACVR1 responsive to a non-canonical ligand, Activin A. There is no etiologic treatment for FOP. However, many efforts are currently ongoing to find specific therapies targeting the receptor activity and the downstream aberrant pathway at different levels or targeting cellular components and/or processes that are important in modifying the local environment leading to bone neo-formation.
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Affiliation(s)
- Serena Cappato
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy.
| | - Francesca Giacopelli
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy.
| | - Roberto Ravazzolo
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy.
| | - Renata Bocciardi
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy.
- UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy.
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Qi Y, Ge J, Ma C, Wu N, Cui X, Liu Z. Activin A regulates activation of mouse neutrophils by Smad3 signalling. Open Biol 2018; 7:rsob.160342. [PMID: 28515224 PMCID: PMC5451541 DOI: 10.1098/rsob.160342] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Accepted: 04/24/2017] [Indexed: 12/19/2022] Open
Abstract
Activin A, a member of the transforming growth factor beta superfamily, acts as a pro-inflammatory factor in acute phase response, and influences the pathological progress of neutrophil-mediated disease. However, whether activin A can exert an effect on the activities of neutrophils remains unclear. In this study, we found that the release of activin A was enhanced from neutrophils of mouse when stimulated with lipopolysaccharide. Furthermore, neutrophils were not only the source of activin A but also the target cells in response to activin A, in which canonical activin signalling components existed, and levels of ACTRIIA, SMAD3 and p-SMAD3 proteins were elevated in activin A-treated neutrophils. Next, the role of activin A was determined in regulation of neutrophils activities. Our data revealed that activin A induced O2− release and reactive oxygen species production, promoted IL-6 release, and enhanced phagocytosis, but failed to attract neutrophils migrating across the trans-well membrane. Moreover, we found that effect of activin A on IL-6 release from the peritoneal neutrophils of mouse was significantly attenuated by in vivo Smad3 knockdown. In summary, these data demonstrate that activin A can exert an effect on neutrophils activation in an autocrine/paracrine manner through Smad3 signalling, suggesting that activin A is an important regulator of neutrophils.
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Affiliation(s)
- Yan Qi
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, People's Republic of China.,Key Laboratory of Neuroimmunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, People's Republic of China
| | - Jingyan Ge
- Key Laboratory of Neuroimmunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, People's Republic of China
| | - Chunhui Ma
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, People's Republic of China
| | - Na Wu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, People's Republic of China
| | - Xueling Cui
- Key Laboratory of Neuroimmunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, People's Republic of China
| | - Zhonghui Liu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, People's Republic of China .,Key Laboratory of Neuroimmunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, People's Republic of China
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Nieto C, Bragado R, Municio C, Sierra-Filardi E, Alonso B, Escribese MM, Domínguez-Andrés J, Ardavín C, Castrillo A, Vega MA, Puig-Kröger A, Corbí AL. The Activin A-Peroxisome Proliferator-Activated Receptor Gamma Axis Contributes to the Transcriptome of GM-CSF-Conditioned Human Macrophages. Front Immunol 2018; 9:31. [PMID: 29434585 PMCID: PMC5796898 DOI: 10.3389/fimmu.2018.00031] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 01/04/2018] [Indexed: 11/30/2022] Open
Abstract
GM-CSF promotes the functional maturation of lung alveolar macrophages (A-MØ), whose differentiation is dependent on the peroxisome proliferator-activated receptor gamma (PPARγ) transcription factor. In fact, blockade of GM-CSF-initiated signaling or deletion of the PPARγ-encoding gene PPARG leads to functionally defective A-MØ and the onset of pulmonary alveolar proteinosis. In vitro, macrophages generated in the presence of GM-CSF display potent proinflammatory, immunogenic and tumor growth-limiting activities. Since GM-CSF upregulates PPARγ expression, we hypothesized that PPARγ might contribute to the gene signature and functional profile of human GM-CSF-conditioned macrophages. To verify this hypothesis, PPARγ expression and activity was assessed in human monocyte-derived macrophages generated in the presence of GM-CSF [proinflammatory GM-CSF-conditioned human monocyte-derived macrophages (GM-MØ)] or M-CSF (anti-inflammatory M-MØ), as well as in ex vivo isolated human A-MØ. GM-MØ showed higher PPARγ expression than M-MØ, and the expression of PPARγ in GM-MØ was found to largely depend on activin A. Ligand-induced activation of PPARγ also resulted in distinct transcriptional and functional outcomes in GM-MØ and M-MØ. Moreover, and in the absence of exogenous activating ligands, PPARγ knockdown significantly altered the GM-MØ transcriptome, causing a global upregulation of proinflammatory genes and significantly modulating the expression of genes involved in cell proliferation and migration. Similar effects were observed in ex vivo isolated human A-MØ, where PPARγ silencing led to enhanced expression of genes coding for growth factors and chemokines and downregulation of cell surface pathogen receptors. Therefore, PPARγ shapes the transcriptome of GM-CSF-dependent human macrophages (in vitro derived GM-MØ and ex vivo isolated A-MØ) in the absence of exogenous activating ligands, and its expression is primarily regulated by activin A. These results suggest that activin A, through enhancement of PPARγ expression, help macrophages to switch from a proinflammatory to an anti-inflammatory polarization state, thus contributing to limit tissue damage and restore homeostasis.
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Affiliation(s)
- Concha Nieto
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Rafael Bragado
- Instituto de Investigación Sanitaria, Fundación Jiménez Díaz, Madrid, Spain
| | - Cristina Municio
- Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Elena Sierra-Filardi
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Bárbara Alonso
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - María M Escribese
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Jorge Domínguez-Andrés
- Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Carlos Ardavín
- Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Antonio Castrillo
- Instituto Investigaciones Biomédicas "Alberto Sols" (IIBM), and Centro Mixto Consejo Superior de Investigaciones Científicas y Universidad Autónoma de Madrid (ICSIC-UAM), Madrid, Spain.,Unidad de Biomedicina (Unidad Asociada al CSIC), IIBM-Universidad Las Palmas de Gran Canaria (ULPGC), and Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, Spain
| | - Miguel A Vega
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Amaya Puig-Kröger
- Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Angel L Corbí
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
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Moisá SJ, Ji P, Drackley JK, Rodriguez-Zas SL, Loor JJ. Transcriptional changes in mesenteric and subcutaneous adipose tissue from Holstein cows in response to plane of dietary energy. J Anim Sci Biotechnol 2017; 8:85. [PMID: 29214018 PMCID: PMC5713657 DOI: 10.1186/s40104-017-0215-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 10/18/2017] [Indexed: 12/15/2022] Open
Abstract
Background Dairy cows can readily overconsume dietary energy during most of the prepartum period, often leading to higher prepartal concentrations of insulin and glucose and excessive body fat deposition. The end result of these physiologic changes is greater adipose tissue lipolysis post-partum coupled with excessive hepatic lipid accumulation and compromised health. Although transcriptional regulation of the adipose response to energy availability is well established in non-ruminants, such regulation in cow adipose tissue depots remains poorly characterized. Results Effects of ad-libitum access to high [HIGH; 1.62 Mcal/kg of dry matter (DM)] or adequate (CON; 1.35 Mcal/kg of DM) dietary energy for 8 wk on mesenteric (MAT) and subcutaneous (SAT) adipose tissue transcript profiles were assessed in non-pregnant non-lactating Holstein dairy cows using a 13,000-sequence annotated bovine oligonucleotide microarray. Statistical analysis revealed 409 and 310 differentially expressed genes (DEG) due to tissue and diet. Bioinformatics analysis was conducted using the Dynamic Impact Approach (DIA) with the KEGG pathway database. Compared with SAT, MAT had more active biological processes related to adipose tissue accumulation (adiponectin secretion) and signs of pro-inflammatory processes due to adipose tissue expansion and macrophage infiltration (generation of ceramides). Feeding the HIGH diet led to changes in mRNA expression of genes associated with cell hypertrophy (regucalcin), activation of adipogenesis (phospholipid phosphatase 1), insulin signaling activation (neuraminidase 1) and angiogenesis (semaphorin 4G, plexin B1). Further, inflammation due to HIGH was underscored by mRNA expression changes associated with oxidative stress response (coenzyme Q3, methyltransferase), ceramide synthesis (N-acylsphingosine amidohydrolase 1), and insulin signaling (interferon regulatory factor 1, phosphoinositide-3-kinase regulatory subunit 1, retinoic acid receptor alpha). Activation of ribosome in cows fed HIGH indicated the existence of greater adipocyte growth rate (M-phase phosphoprotein 10, NMD3 ribosome export adaptor). Conclusions The data indicate that long-term ad-libitum access to a higher-energy diet led to transcriptional changes in adipose tissue that stimulated hypertrophy and the activity of pathways associated with a slight but chronic inflammatory response. Further studies would be helpful in determining the extent to which mRNA results also occur at the protein level.
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Affiliation(s)
- S J Moisá
- Department of Animal Sciences, Auburn University, 231 Upchurch Hall, 361 Mell Street, Auburn, AL 36849-5426 USA
| | - P Ji
- Department of Animal Sciences, University of Illinois, Urbana, 61801 USA
| | - J K Drackley
- Department of Animal Sciences, University of Illinois, Urbana, 61801 USA
| | - S L Rodriguez-Zas
- Department of Animal Sciences, University of Illinois, Urbana, 61801 USA
| | - J J Loor
- Department of Animal Sciences, University of Illinois, Urbana, 61801 USA
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Del Zotto G, Antonini F, Azzari I, Ortolani C, Tripodi G, Giacopelli F, Cappato S, Moretta L, Ravazzolo R, Bocciardi R. Peripheral Blood Mononuclear Cell Immunophenotyping in Fibrodysplasia Ossificans Progressiva Patients: Evidence for Monocyte DNAM1 Up-regulation. CYTOMETRY PART B-CLINICAL CYTOMETRY 2017; 94:613-622. [PMID: 28985649 DOI: 10.1002/cyto.b.21594] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 09/10/2017] [Accepted: 10/02/2017] [Indexed: 11/09/2022]
Abstract
BACKGROUND Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder caused by sporadic heterozygous mutations in ACVR1 gene which progressively leads to severe heterotopic ossification. FOP is characterized by episodic flare-ups triggered by different factors such as viral infections, tissue injuries, vaccinations, or occurring without a recognizable cause. The sporadic course of the disease, the documented presence of an important inflammatory reaction in early lesions and the partial response to corticosteroids support the idea that the immune system, and in particular the innate component, may play a role in FOP pathogenesis. However, an extensive expression profile of the peripheral blood mononuclear cells (PBMC) of FOP patients has never been done. METHODS In this study, we carried out a wide PBMC immunophenotyping on a cohort of FOP patients and matching controls by multiparametric analysis of the expression of a panel of 37 markers associated with migration, adhesion, inhibition, activation, and cell death of circulating immune cells. RESULTS We observed a statistically significant increase of the expression of DNAM1 receptor in patients' monocytes as compared to controls, and little but significant differences in the expression profile of CXCR1 (CD181), CD62L, CXCR4 (CD184), and HLA-DR molecules. CONCLUSIONS DNAM1 had been previously shown to play a pivotal role in monocyte migration through the endothelial barrier and the increased expression detected in patients' monocytes might suggest a role of this surface receptor during the early phases of FOP flare-ups in which the activation of the immune response is believed to represent a crucial event. © 2017 International Clinical Cytometry Society.
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Affiliation(s)
| | | | - Irma Azzari
- IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Claudio Ortolani
- Department of Biomolecular Sciences, University of Urbino, Pesaro-Urbino, Italy
| | | | - Francesca Giacopelli
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, Università degli Studi di Genova, Genova, Italy
| | - Serena Cappato
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, Università degli Studi di Genova, Genova, Italy
| | - Lorenzo Moretta
- Department of Immunology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Roberto Ravazzolo
- IRCCS Istituto Giannina Gaslini, Genova, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, Università degli Studi di Genova, Genova, Italy
| | - Renata Bocciardi
- IRCCS Istituto Giannina Gaslini, Genova, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, Università degli Studi di Genova, Genova, Italy
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Activin in acute pancreatitis: Potential risk-stratifying marker and novel therapeutic target. Sci Rep 2017; 7:12786. [PMID: 28986573 PMCID: PMC5630611 DOI: 10.1038/s41598-017-13000-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 09/12/2017] [Indexed: 02/07/2023] Open
Abstract
Acute Pancreatitis is a substantial health care challenge with increasing incidence. Patients who develop severe disease have considerable mortality. Currently, no reliable predictive marker to identify patients at risk for severe disease exists. Treatment is limited to rehydration and supporting care suggesting an urgent need to develop novel approaches to improve standard care. Activin is a critical modulator of inflammatory responses, but has not been assessed in pancreatitis. Here, we demonstrate that serum activin is elevated and strongly correlates with disease severity in two established murine models of acute pancreatitis induced by either cerulein or IL-12 + IL-18. Furthermore, in mice, inhibition of activin conveys survival benefits in pancreatitis. In addition, serum activin levels were measured from a retrospective clinical cohort of pancreatitis patients and high activin levels in patients at admission are predictive of worse outcomes, indicated by longer overall hospital and intensive care unit stays. Taken together, activin is a novel candidate as a clinical marker to identify those acute pancreatitis patients with severe disease who would benefit from aggressive treatment and activin may be a therapeutic target in severe acute pancreatitis.
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D'Hooghe T, Kyriakidi K, Karassa FB, Politis D, Skamnelos A, Christodoulou DK, Katsanos KH. Biomarker Development in Chronic Inflammatory Diseases. BIOMARKERS FOR ENDOMETRIOSIS 2017. [PMCID: PMC7122305 DOI: 10.1007/978-3-319-59856-7_3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chronic inflammatory diseases, such as inflammatory bowel disease—namely, Crohn’s disease and ulcerative colitis—psoriasis, multiple sclerosis, rheumatoid arthritis, and many others affect millions of people worldwide, causing a high burden of disease, socioeconomic impact, and healthcare cost. These diseases have common features including autoimmune pathogenesis and frequent co morbidity. The treatment of these chronic inflammatory diseases usually requires long-term immunosuppressive therapies with undesirable side effects. The future of chronic inflammatory disease prevention, detection, and treatment will be greatly influenced by the use of more effective biomarkers with enhanced performance. Given the practical issues of collecting tissue samples in inflammatory diseases, biomarkers derived from body fluids have great potential for optimized patient management through the circumvention of the abovementioned limitations. In this chapter, peripheral blood, urine, and cerebrospinal fluid biomarkers used in chronic inflammatory conditions are reviewed. In detail, this chapter reviews biomarkers to fore used or emerging to be used in patients with chronic inflammatory conditions. Those include inflammatory bowel diseases, chronic inflammatory conditions of the liver, biliary tract, pancreas, psoriasis, atopic disease, inflammatory skin diseases, rheumatic diseases, demyelination, and also the chronic inflammatory component of various other diseases in general medicine—including diabetes, cardiovascular disease, renal disease, and chronic obstructive pulmonary disease. Development of personalized medicine is closely linked to biomarkers, which may serve as the basis for diagnosis, drug discovery, and monitoring of diseases.
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Affiliation(s)
- Thomas D'Hooghe
- 0000 0001 0668 7884grid.5596.fDepartment of Development and Regeneration Organ Systems, Group Biomedical Sciences, KU Leuven (University of Leuven), Leuven, Belgium
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Cepika AM, Banchereau R, Segura E, Ohouo M, Cantarel B, Goller K, Cantrell V, Ruchaud E, Gatewood E, Nguyen P, Gu J, Anguiano E, Zurawski S, Baisch JM, Punaro M, Baldwin N, Obermoser G, Palucka K, Banchereau J, Amigorena S, Pascual V. A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis. J Exp Med 2017; 214:3449-3466. [PMID: 28935693 PMCID: PMC5679164 DOI: 10.1084/jem.20170412] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 07/25/2017] [Accepted: 09/08/2017] [Indexed: 12/26/2022] Open
Abstract
The etiology of autoinflammation in systemic juvenile idiopathic arthritis is unclear. Cepika et al. use integrated analysis of multidimensional blood stimulation data, applied to patients while off treatment and in complete remission, to reveal underlying cellular and molecular mechanisms that might predispose to disease. The etiology of sporadic human chronic inflammatory diseases remains mostly unknown. To fill this gap, we developed a strategy that simultaneously integrates blood leukocyte responses to innate stimuli at the transcriptional, cellular, and secreted protein levels. When applied to systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory disease of unknown etiology, this approach identified gene sets associated with specific cytokine environments and activated leukocyte subsets. During disease remission and off treatment, sJIA patients displayed dysregulated responses to TLR4, TLR8, and TLR7 stimulation. Isolated sJIA monocytes underexpressed the IL-1 inhibitor aryl hydrocarbon receptor (AHR) at baseline and accumulated higher levels of intracellular IL-1β after stimulation. Supporting the demonstration that AHR down-regulation skews monocytes toward macrophage differentiation, sJIA monocytes differentiated in vitro toward macrophages, away from the dendritic cell phenotype. This might contribute to the increased incidence of macrophage activation syndrome in these patients. Integrated analysis of high-dimensional data can thus unravel immune alterations predisposing to complex inflammatory diseases.
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Affiliation(s)
| | | | - Elodie Segura
- Institut National de la Santé et de la Recherche Medicale U932, Institut Curie, PSL Research University, Paris, France
| | - Marina Ohouo
- Baylor Institute for Immunology Research, Dallas, TX
| | | | | | | | - Emily Ruchaud
- Baylor Institute for Immunology Research, Dallas, TX
| | | | - Phuong Nguyen
- Baylor Institute for Immunology Research, Dallas, TX
| | - Jinghua Gu
- Baylor Institute for Immunology Research, Dallas, TX
| | | | | | | | | | | | | | - Karolina Palucka
- Baylor Institute for Immunology Research, Dallas, TX.,The Jackson Laboratory for Genomic Medicine, Farmington, CT
| | | | - Sebastian Amigorena
- Institut National de la Santé et de la Recherche Medicale U932, Institut Curie, PSL Research University, Paris, France
| | - Virginia Pascual
- Baylor Institute for Immunology Research, Dallas, TX .,University of Texas Southwestern Medical Center, Dallas, TX.,Texas Scottish Rite Hospital for Children, Dallas, TX
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Margutti KMDM, Schuch NJ, Schwanke CHA. Inflammatory markers, sarcopenia and its diagnostic criteria among the elderly: a systematic review. REVISTA BRASILEIRA DE GERIATRIA E GERONTOLOGIA 2017. [DOI: 10.1590/1981-22562017020.160155] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Abstract Objective: To identify the relationship between inflammatory markers and sarcopenia, and the diagnostic criteria of the condition among the elderly. Methods: A systematic review was performed based on the consultation of the PubMed and LILACS databases. Eligible original articles were those involving individuals aged 60 years or more, which investigated sarcopenia [low muscle mass (MM) associated with poor muscle strength and/or reduced physical performance, according to the European Working Group on Sarcopenia in Older People consensus (EWGSOP)] or its diagnostic criteria, published in English or Portuguese, between 2010-2015. Results: Four articles were included in the review, the principle results of which were: the growth differentiation factor (GDF-15) exhibited a negative correlation with MM, handgrip strength and gait speed; the insulin-like growth factor-1 (IGF-1) correlated positively with MM; follistatin exhibited a weak correlation with physical performance; activin A and myostatin did not correlate with the diagnostic criteria; the highest tercile of extracellular heat shock protein 72 (eHsp72) was associated with lower median levels of MM, handgrip strength and gait speed; elderly persons with low MM had higher serum ferritin concentrations; women with low MM exhibited lower serum concentration levels of C-reactive protein (CRP). Conclusion: the six investigated inflammatory markers (GDF-15, IGF-1, follistatin, eHsp72, ferritin and CRP) were associated with the diagnostic criteria for sarcopenia, but not with sarcopenia itself. As research in this area is still developing, additional studies are required to broaden knowledge and eventually establish the role of these markers in the diagnosis and management of sarcopenia.
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Porter LM, Radulović ŽM, Mulenga A. A repertoire of protease inhibitor families in Amblyomma americanum and other tick species: inter-species comparative analyses. Parasit Vectors 2017; 10:152. [PMID: 28330502 PMCID: PMC5361777 DOI: 10.1186/s13071-017-2080-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Accepted: 03/06/2017] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Protease inhibitors (PIs) are important regulators of physiology and represent anti-parasitic druggable and vaccine targets. We conducted bioinformatic analyses of genome and transcriptome data to determine the protease inhibitor (PI) repertoire in Amblyomma americanum and in 25 other ixodid tick species. For A. americanum, we compared the PI repertoires in fed and unfed, male and female A. americanum ticks. We also analyzed PI repertoires of female 48, 96 and 120 h-fed midgut (MG) and salivary gland (SG) tissues. RESULTS We found 1,595 putative non-redundant PI sequences across 26 ixodid tick species. Ticks express PIs from at least 18 different families: I1, I2, I4, I8, I21, I25, I29, I31, I32, I35, I39, I43, I51, I53, I63, I68, I72 and I74 (MEROPS). The largest PI families were I2, I4 and I8 and lowest in I21, I31, I32, I35 and I68. The majority (75%) of tick PIs putatively inhibit serine proteases, with ~11 and 9% putatively regulating cysteine or metalloprotease-mediated pathways, respectively, and ~4% putatively regulating multiple/mixed protease types. In A. americanum, we found 370 PIs in female and 354 in male ticks. In A. americanum we found 231 and 442 in unfed and fed ticks, respectively. In females, we found 206 and 164 PIs in SG and MG, respectively. The majority of highly cross-tick species conserved PIs were in families I1, I2, I8, I21, I25, I29, I39 and I43. CONCLUSIONS Ticks appear to express large and diverse repertoires of PIs that primarily target serine protease-mediated pathways. We speculate that PI families with the highest repertoires may contain functionally redundant members while those with the lowest repertoires are functionally non-redundant PIs. We found some highly conserved PIs in the latter category, which we propose as potential candidates for broad-spectrum anti-tick vaccine candidates or druggable targets in tick control.
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Affiliation(s)
- Lindsay M Porter
- Department of Veterinary Pathobiology, Texas A&M University College of Veterinary Medicine and Biomedical Sciences, 4647 TAMU, College Station, TX, 77843, USA
| | - Željko M Radulović
- Department of Veterinary Pathobiology, Texas A&M University College of Veterinary Medicine and Biomedical Sciences, 4647 TAMU, College Station, TX, 77843, USA
| | - Albert Mulenga
- Department of Veterinary Pathobiology, Texas A&M University College of Veterinary Medicine and Biomedical Sciences, 4647 TAMU, College Station, TX, 77843, USA.
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Mendell JR, Sahenk Z, Al-Zaidy S, Rodino-Klapac LR, Lowes LP, Alfano LN, Berry K, Miller N, Yalvac M, Dvorchik I, Moore-Clingenpeel M, Flanigan KM, Church K, Shontz K, Curry C, Lewis S, McColly M, Hogan MJ, Kaspar BK. Follistatin Gene Therapy for Sporadic Inclusion Body Myositis Improves Functional Outcomes. Mol Ther 2017; 25:870-879. [PMID: 28279643 DOI: 10.1016/j.ymthe.2017.02.015] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Revised: 02/15/2017] [Accepted: 02/15/2017] [Indexed: 12/25/2022] Open
Abstract
Sporadic inclusion body myositis, a variant of inflammatory myopathy, has features distinct from polymyositis/dermatomyositis. The disease affects men more than women, most commonly after age 50. Clinical features include weakness of the quadriceps, finger flexors, ankle dorsiflexors, and dysphagia. The distribution of weakness is similar to Becker muscular dystrophy, where we previously reported improvement following intramuscular injection of an isoform of follistatin (FS344) by AAV1. For this clinical trial, rAAV1.CMV.huFS344, 6 × 1011 vg/kg, was delivered to the quadriceps muscles of both legs of six sporadic inclusion body myositis subjects. The primary outcome for this trial was distance traveled for the 6-min walk test. The protocol included an exercise regimen for each participant. Performance, annualized to a median 1-year change, improved +56.0 m/year for treated subjects compared to a decline of -25.8 m/year (p = 0.01) in untreated subjects (n = 8), matched for age, gender, and baseline measures. Four of the six treated subjects showed increases ranging from 58-153 m, whereas two were minimally improved (5-23 m). Treatment effects included decreased fibrosis and improved regeneration. These findings show promise for follistatin gene therapy for mild to moderately affected, ambulatory sporadic inclusion body myositis patients. More advanced disease with discernible muscle loss poses challenges.
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Affiliation(s)
- Jerry R Mendell
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA; Department of Neurology, The Ohio State University, Columbus, OH 43210, USA.
| | - Zarife Sahenk
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA; Department of Neurology, The Ohio State University, Columbus, OH 43210, USA
| | - Samiah Al-Zaidy
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA
| | - Louise R Rodino-Klapac
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA
| | - Linda P Lowes
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Neurology, The Ohio State University, Columbus, OH 43210, USA; Clinical Therapies, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Lindsay N Alfano
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Neurology, The Ohio State University, Columbus, OH 43210, USA; Clinical Therapies, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Katherine Berry
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Neurology, The Ohio State University, Columbus, OH 43210, USA; Clinical Therapies, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Natalie Miller
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Neurology, The Ohio State University, Columbus, OH 43210, USA; Clinical Therapies, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Mehmet Yalvac
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Igor Dvorchik
- Biostatics Research Core, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | | | - Kevin M Flanigan
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA; Department of Neurology, The Ohio State University, Columbus, OH 43210, USA
| | - Kathleen Church
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Kim Shontz
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Choumpree Curry
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Sarah Lewis
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Markus McColly
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Mark J Hogan
- Vascular and Interventional Radiology, Department of Radiology, Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Brian K Kaspar
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA
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Testicular activin and follistatin levels are elevated during the course of experimental autoimmune epididymo-orchitis in mice. Sci Rep 2017; 7:42391. [PMID: 28205525 PMCID: PMC5304336 DOI: 10.1038/srep42391] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 01/10/2017] [Indexed: 12/26/2022] Open
Abstract
Experimental autoimmune epididymo-orchitis (EAEO) is a model of chronic inflammation, induced by immunisation with testicular antigens, which reproduces the pathology of some types of human infertility. Activins A and B regulate spermatogenesis and steroidogenesis, but are also pro-inflammatory, pro-fibrotic cytokines. Expression of the activins and their endogenous antagonists, inhibin and follistatin, was examined in murine EAEO. Adult untreated and adjuvant-treated control mice showed no pathology. All mice immunised with testis antigens developed EAEO by 50 days, characterised by loss of germ cells, immune cell infiltration and fibrosis in the testis, similar to biopsies from human inflamed testis. An increase of total CD45+ leukocytes, comprising CD3+ T cells, CD4 + CD8− and CD4 + CD25+ T cells, and a novel population of CD4 + CD8+ double positive T cells was also detected in EAEO testes. This was accompanied by increased expression of TNF, MCP-1 and IL-10. Activin A and B and follistatin protein levels were elevated in EAEO testes, with peak activin expression during the active phase of the disease, whereas mRNA expression of the inhibin B subunits (Inha and Inhbb) and activin receptor subunits (Acvr1b and Acvr2b) were downregulated. These data suggest that activin–follistatin regulation may play a role during the development of EAEO.
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