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Truffinet F, Arco-Hierves A, Shalabi H, Pascaud J, Mazet P, Rivière E, E Silva-Saffar S, Fabbri L, Leboucher S, Besse L, Messaoudi C, Attina A, David A, Vagner S, Nocturne G, Mariette X, Bechara R. m 6A RNA methylation controls salivary gland epithelial cell function and has a protective role in Sjögren's disease. Ann Rheum Dis 2024:ard-2024-226224. [PMID: 39299724 DOI: 10.1136/ard-2024-226224] [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: 06/05/2024] [Accepted: 08/23/2024] [Indexed: 09/22/2024]
Abstract
OBJECTIVES The RNA epitranscriptomic modification known as N6-methyladenosine (m6A) represents a novel mechanism of gene regulation that is poorly understood in human autoimmune diseases. Our research explores the role of this RNA m6A modification in salivary gland epithelial cells (SGEC) and its impact on the pathogenesis of Sjögren's disease (SjD). METHODS SGECs from SjD patients and controls were analysed for m6A writers METTL3 and METTL14 expression using RNA-seq, quantitative PCR and immunohistochemistry. Functional assays assessed the impact of METTL3 knockdown or pharmacological inhibition on proinflammatory gene expression and immune cell interactions (using transwell and coculture systems). Mechanistic studies examined METTL3-mediated m6A modifications in double-stranded RNA (dsRNA) formation through immunofluorescence. Unsupervised clustering identified patterns of interferon activation in salivary glands and their correlation with m6A writers. RESULTS METTL3 and METTL14 were elevated in SGEC from SjD patients in comparison to controls. Paradoxically, inhibiting METTL3 increased proinflammatory gene expression, enhancing SGEC's ability to attract immune cells and activate B cells. Conversely, inhibiting the eraser FTO had the opposite effect. METTL3-mediated m6A modifications prevented dsRNA formation and IFN signalling activation. SGEC from SjD showed insufficient METTL3 upregulation compared with controls in response to inflammatory triggers, indicating a limited capacity to regulate the inflammatory response. SjD patients with elevated disease activity and higher interferon signature exhibit reduced METTL3 expression. CONCLUSIONS Impairment of m6A modifications in SGEC in response to inflammatory triggers favour the formation of dsRNA, potentially amplifying the interferon loop and contributing to SjD pathogenesis.
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Affiliation(s)
- Frederic Truffinet
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Inserm U1184, Le Kremlin-Bicetre, France
| | - Alejandro Arco-Hierves
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Inserm U1184, Le Kremlin-Bicetre, France
- Fondation Arthritis, Neuilly Sur Seine, France
| | - Hosnia Shalabi
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Inserm U1184, Le Kremlin-Bicetre, France
| | - Juliette Pascaud
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Inserm U1184, Le Kremlin-Bicetre, France
| | - Paul Mazet
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Inserm U1184, Le Kremlin-Bicetre, France
| | - Elodie Rivière
- UMR 1125, Sorbonne Paris Nord University, AP-HP, GHUPSSD, Department of Rheumatology, INSERM, Bobigny, France
| | - Sacha E Silva-Saffar
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Inserm U1184, Le Kremlin-Bicetre, France
| | - Lucilla Fabbri
- Institut Curie, PSL Research University, CNRS UMR 3348, INSERM U1278, Orsay, France
- Université Paris-Saclay, CNRS UMR 3348, INSERM U1278, Orsay, France
| | - Sophie Leboucher
- Histology Platform, Institut Curie, PSL Research University, Université Paris-Saclay, Orsay, France
| | - Laetitia Besse
- Multimodal Imaging Center, Institut Curie, CNRS UAR2016, INSERM US43, PSL Research University, Université Paris-Saclay, Orsay, France
| | - Cedric Messaoudi
- Multimodal Imaging Center, Institut Curie, CNRS UAR2016, INSERM US43, PSL Research University, Université Paris-Saclay, Orsay, France
| | - Aurore Attina
- PPC, IRBM, INM, Univ Montpellier, CHU Montpellier, INSERM CNRS, Montpellier, France
| | - Alexandre David
- PPC, IRBM, INM, Univ Montpellier, CHU Montpellier, INSERM CNRS, Montpellier, France
- IRCM, Univ Montpellier, ICM, INSERM, Montpellier, France
| | - Stephan Vagner
- Institut Curie, PSL Research University, CNRS UMR 3348, INSERM U1278, Orsay, France
- Université Paris-Saclay, CNRS UMR 3348, INSERM U1278, Orsay, France
| | - Gaetane Nocturne
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Inserm U1184, Le Kremlin-Bicetre, France
- Hôpitaux de Paris, Hôpital Bicêtre, Department of Rheumatology, APHP, Le Kremlin Bicêtre, France
| | - Xavier Mariette
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Inserm U1184, Le Kremlin-Bicetre, France
- Hôpitaux de Paris, Hôpital Bicêtre, Department of Rheumatology, APHP, Le Kremlin Bicêtre, France
| | - Rami Bechara
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB/IDMIT), Inserm U1184, Le Kremlin-Bicetre, France
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Vasileva F, Font-Lladó R, Carreras-Badosa G, Cazorla-González J, López-Bermejo A, Prats-Puig A. Integrated neuromuscular training intervention applied in schools induces a higher increase in salivary high molecular weight adiponectin and a more favorable body mass index, cardiorespiratory fitness and muscle strength in children as compared to the traditional physical education classes. Front Public Health 2024; 12:1337958. [PMID: 38756879 PMCID: PMC11096568 DOI: 10.3389/fpubh.2024.1337958] [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: 11/13/2023] [Accepted: 04/19/2024] [Indexed: 05/18/2024] Open
Abstract
Background High-molecular-weight adiponectin (HMW-adiponectin) is a cardio-metabolic health protector. Objectives: (1) to compare body mass index (BMI), cardiorespiratory fitness (CRF) and muscle strength (MS) in healthy school-children depending on their baseline salivary-HMW-adiponectin concentration; and (2) to apply a 3-month integrated neuromuscular training (INT) and evaluate its effects on salivary-HMW-adiponectin concentration, BMI, CRF and MS in the same children. Additional goal: to identify if any potential changes during the 3-month period may be related to a potential change in salivary-HMW-adiponectin concentration. Methods Ninety children (7.4 ± 0.3 years) were recruited in primary schools and randomly allocated into control or intervention group. The intervention consisted of a 3-month INT applied during physical education (PE) classes, twice-weekly, while the control group had traditional PE classes. Body mass and height were measured, BMI was calculated and HMW-adiponectin was quantified in saliva. To assess CRF and MS, 800 m-run and hand-dynamometry were applied, respectively. All measurements were performed twice, at baseline and after 3 months. Results Children with higher baseline salivary-HMW-adiponectin have more favorable BMI (p = 0.006) and slightly higher CRF (p = 0.017) in comparison to the children with lower baseline salivary-HMW-adiponectin. There were no big changes after the 3-month-period neither in the control, nor the INT group. However, it is worthy to note that the INT induced slightly higher increase in salivary-HMW-adiponectin (p = 0.007), and a slightly higher improvement in BMI (p = 0.028), CRF (p = 0.043) and MS (p = 0.003), as compared to the traditional PE classes. Finally, the INT-induced improvement in CRF was associated with the increased post-salivary-HMW-adiponectin concentration (p = 0.022). Conclusion Main findings may suggest the potential utility of an INT as a cost-effective strategy that can be applied in schools to induce cardio-protective effects in school-children.
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Affiliation(s)
- Fidanka Vasileva
- Pediatric Endocrinology Research Group, Girona Institute for Biomedical Research, Girona, Spain
- University School of Health and Sport, University of Girona, Girona, Spain
| | - Raquel Font-Lladó
- University School of Health and Sport, University of Girona, Girona, Spain
- Research Group of Culture and Education, Institute of Educational Research, University of Girona, Girona, Spain
| | - Gemma Carreras-Badosa
- Pediatric Endocrinology Research Group, Girona Institute for Biomedical Research, Girona, Spain
| | | | - Abel López-Bermejo
- Pediatric Endocrinology Research Group, Girona Institute for Biomedical Research, Girona, Spain
- Department of Medical Sciences, University of Girona, Girona, Spain
- Pediatric Endocrinology, Dr. Josep Trueta Hospital, Girona, Spain
| | - Anna Prats-Puig
- University School of Health and Sport, University of Girona, Girona, Spain
- Research Group of Clinical Anatomy, Embryology and Neuroscience, Department of Medical Sciences, University of Girona, Girona, Spain
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Kim JW, Kim JM, Choi ME, Jeon EJ, Park JM, Kim YM, Choi JS. Adiponectin is associated with inflammaging and age-related salivary gland lipid accumulation. Aging (Albany NY) 2023; 15:1840-1858. [PMID: 36988495 PMCID: PMC10085617 DOI: 10.18632/aging.204618] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 03/17/2023] [Indexed: 03/29/2023]
Abstract
Dry mouth is frequently observed in the elderly, and enhanced lipid accumulation plays a critical role in cellular senescence in the salivary gland (SG). We investigated the mechanisms that mediate lipogenesis-associated SG senescence. Adult (28.6 ± 6.6 y.o. and 43.3 ± 1.5 y.o.) and aged (82.0 ± 4.3 y.o. and 88.0 ± 4.3 y.o.) human parotid and submandibular glands were compared with respect to histologic findings, 8-OHdG (8-hydroxy 2 deoxyguanosine) expression patterns, TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) and SA-β-gal (senescence-associated β-galactosidase) assay results. Also, microarray analysis was performed on RNA extracted from adult and aged SG to identify DEGs (differentially expressed genes). The effects of silencing ADIPOQ (Adiponectin) were evaluated by quantifying cell proliferation, immunohistochemical staining for cellular senescence and inflammation-associated proteins, SA-β-gal assays, RT-PCR, and western blot. Histological findings demonstrated the presence of more lipocytes, chronic inflammation, fibrosis, and lymphocytic infiltration in old SG. In addition, old tissues demonstrated higher expressions of SA-β-gal, more apoptotic cells in TUNEL assays, and higher oxidative stress by 8-OHdG immunostaining. Microarray analysis showed lipogenesis was significantly upregulated in old tissues. Silencing of ADIPOQ (a lipogenesis-related gene) reduced inflammation and SA-β-gal levels and increased cell proliferation and the expressions of amylase and aquaporin 5 in human SG epithelial cells. The study shows ADIPOQ is a potential target molecule for the modulation of lipogenesis associated with SG senescence.
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Adiponectin Deregulation in Systemic Autoimmune Rheumatic Diseases. Int J Mol Sci 2021; 22:ijms22084095. [PMID: 33920997 PMCID: PMC8071452 DOI: 10.3390/ijms22084095] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/08/2021] [Accepted: 04/13/2021] [Indexed: 02/06/2023] Open
Abstract
Deregulation of adiponectin is found in systemic autoimmune rheumatic diseases (SARDs). Its expression is downregulated by various inflammatory mediators, but paradoxically, elevated serum levels are present in SARDs with high inflammatory components, such as rheumatoid arthritis and systemic lupus erythematosus. Circulating adiponectin is positively associated with radiographic progression in rheumatoid arthritis as well as with cardiovascular risks and lupus nephritis in systemic lupus erythematosus. However, in SARDs with less prominent inflammation, such as systemic sclerosis, adiponectin levels are low and correlate negatively with disease activity. Regulators of adiponectin gene expression (PPAR-γ, Id3, ATF3, and SIRT1) and inflammatory cytokines (interleukin 6 and tumor necrosis factor α) are differentially expressed in SARDs and could therefore influence total adiponectin levels. In addition, anti-inflammatory therapy could also have an impact, as tocilizumab treatment is associated with increased serum adiponectin. However, anti-tumor necrosis factor α treatment does not seem to affect its levels. Our review provides an overview of studies on adiponectin levels in the bloodstream and other biological samples from SARD patients and presents some possible explanations why adiponectin is deregulated in the context of therapy and gene regulation.
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Crosson SM, Marques A, Dib P, Dotson CD, Munger SD, Zolotukhin S. Taste Receptor Cells in Mice Express Receptors for the Hormone Adiponectin. Chem Senses 2020; 44:409-422. [PMID: 31125082 DOI: 10.1093/chemse/bjz030] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The metabolic hormone adiponectin is secreted into the circulation by adipocytes and mediates key biological functions, including insulin sensitivity, adipocyte development, and fatty acid oxidation. Adiponectin is also abundant in saliva, where its functions are poorly understood. Here we report that murine taste receptor cells (TRCs) express specific adiponectin receptors and may be a target for salivary adiponectin. This is supported by the presence of all three known adiponectin receptors in transcriptomic data obtained by RNA-seq analysis of purified circumvallate (CV) taste buds. As well, immunohistochemical analysis of murine CV papillae showed that two adiponectin receptors, ADIPOR1 and T-cadherin, are localized to subsets of TRCs. Immunofluorescence for T-cadherin was primarily co-localized with the Type 2 TRC marker phospholipase C β2, suggesting that adiponectin signaling could impact sweet, bitter, or umami taste signaling. However, adiponectin null mice showed no differences in behavioral lick responsiveness compared with wild-type controls in brief-access lick testing. AAV-mediated overexpression of adiponectin in the salivary glands of adiponectin null mice did result in a small but significant increase in behavioral lick responsiveness to the fat emulsion Intralipid. Together, these results suggest that salivary adiponectin can affect TRC function, although its impact on taste responsiveness and peripheral taste coding remains unclear.
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Affiliation(s)
- Sean M Crosson
- Department of Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Gainesville, FL, USA.,Center for Smell and Taste, University of Florida, Gainesville, FL, USA.,Graduate Program in Biomedical Sciences, University of Florida, Gainesville, FL, USA
| | - Andrew Marques
- Department of Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Gainesville, FL, USA
| | - Peter Dib
- Graduate Program in Biomedical Sciences, University of Florida, Gainesville, FL, USA.,Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL, USA
| | - Cedrick D Dotson
- Center for Smell and Taste, University of Florida, Gainesville, FL, USA.,Department of Neuroscience, University of Florida, Gainesville, FL, USA
| | - Steven D Munger
- Center for Smell and Taste, University of Florida, Gainesville, FL, USA.,Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.,Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism; University of Florida, Gainesville, FL, USA
| | - Sergei Zolotukhin
- Department of Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Gainesville, FL, USA.,Center for Smell and Taste, University of Florida, Gainesville, FL, USA
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Robak O, Kuzmina Z, Winkler A, Kalhs P, Rabitsch W, Greinix H. Adiponectin and resistin in acute and chronic graft-vs-host disease patients undergoing allogeneic hematopoietic stem cell transplantation. Croat Med J 2016; 57:255-65. [PMID: 27374827 PMCID: PMC4937231 DOI: 10.3325/cmj.2016.57.255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Aim To investigate the association of adiponectin and resistin levels in patients undergoing hematopoietic stem cell transplantation (HSCT) with the clinical outcome, including the occurrence of acute and chronic graft-vs-host disease (GVHD), non-relapse mortality, and overall survival. Methods We prospectively collected serum samples from 40 patients undergoing either autologous (n = 12; 10 male) or allogeneic (n = 28; 11 male) HSCT for up to 12 months post HSCT and determined adiponectin and resistin serum concentrations using enzyme-linked immunosorbent assay. Results There were no significant differences in adiponectin levels (18.5 vs 9.3 µg/mL, P = 0.071) and adiponectin/BMI ratio (0.82 vs 0.39, P = 0.068) between patients with acute GVHD grades 2-4 and autologous controls. However, resistin values were significantly lower in patients with acute GVHD grades 2-4 than in autologous controls (4.6 vs 7.3 ng/mL, P = 0.030). Adiponectin levels were higher in patients with chronic GVHD (n = 17) than in autologous controls (13.5 vs 7.6 µg/mL, P = 0.051), but the difference was not significant. Adiponectin/BMI ratio was significantly higher in patients with chronic GVHD than in autologous controls (0.59 vs 0.25, P = 0.006). Patients dying from relapse also had significantly lower adiponectin levels (8.2 µg/mL) and adiponectin/BMI ratio (0.3) on admission than surviving allogeneic (15.8 µg/mL, P = 0.030 and 0.7, P = 0.004) and surviving autologous patients (19.2 µg/mL, P = 0.031 and 0.7, P = 0.021). Conclusion Adiponectin and resistin levels were altered in patients with acute and chronic GVHD compared to autologous controls and were associated with overall survival and relapse mortality in patients undergoing allogeneic HSCT.
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Affiliation(s)
- Oliver Robak
- Oliver Robak, Department of Internal Medicine I, Intensive Care Unit, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria,
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Abella V, Scotece M, Conde J, López V, Lazzaro V, Pino J, Gómez-Reino JJ, Gualillo O. Adipokines, metabolic syndrome and rheumatic diseases. J Immunol Res 2014; 2014:343746. [PMID: 24741591 PMCID: PMC3987880 DOI: 10.1155/2014/343746] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 01/10/2014] [Accepted: 01/10/2014] [Indexed: 02/06/2023] Open
Abstract
The metabolic syndrome (MetS) is a cluster of cardiometabolic disorders that result from the increasing prevalence of obesity. The major components of MetS include insulin resistance, central obesity, dyslipidemia, and hypertension. MetS identifies the central obesity with increased risk for cardiovascular diseases (CVDs) and type-2 diabetes mellitus (T2DM). Patients with rheumatic diseases, such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis, have increased prevalence of CVDs. Moreover, CVD risk is increased when obesity is present in these patients. However, traditional cardiovascular risk factors do not completely explain the enhanced cardiovascular risk in this population. Thus, MetS and the altered secretion patterns of proinflammatory adipokines present in obesity could be the link between CVDs and rheumatic diseases. Furthermore, adipokines have been linked to the pathogenesis of MetS and its comorbidities through their effects on vascular function and inflammation. In the present paper, we review recent evidence of the role played by adipokines in the modulation of MetS in the general population, and in patients with rheumatic diseases.
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Affiliation(s)
- Vanessa Abella
- SERGAS, Research Laboratory 9, NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Institute of Medical Research (IDIS), Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain ; Department of Molecular and Cellular Biology, University of Coruña (UDC), 15071 A Coruña, Spain
| | - Morena Scotece
- SERGAS, Research Laboratory 9, NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Institute of Medical Research (IDIS), Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Javier Conde
- SERGAS, Research Laboratory 9, NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Institute of Medical Research (IDIS), Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Verónica López
- SERGAS, Research Laboratory 9, NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Institute of Medical Research (IDIS), Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Verónica Lazzaro
- SERGAS, Research Laboratory 9, NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Institute of Medical Research (IDIS), Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain ; University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Jesús Pino
- SERGAS, Division of Orthopaedics Surgery and Traumatology, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Juan J Gómez-Reino
- SERGAS, Research Laboratory 9, NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Institute of Medical Research (IDIS), Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Oreste Gualillo
- SERGAS, Research Laboratory 9, NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Institute of Medical Research (IDIS), Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
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Pflugfelder SC, Corrales RM, de Paiva CS. T helper cytokines in dry eye disease. Exp Eye Res 2013; 117:118-25. [PMID: 24012834 PMCID: PMC3855838 DOI: 10.1016/j.exer.2013.08.013] [Citation(s) in RCA: 126] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 08/13/2013] [Accepted: 08/16/2013] [Indexed: 01/28/2023]
Abstract
Dry eye is an inflammatory disease that results from activation of innate inflammatory pathways in resident ocular surface cells, as well as cytokines produced by recruited T helper (Th) cells. Cytokines produced by the infiltrating Th cells alter the normal cytokine balance on the ocular surface and cause ocular surface epithelial pathology. Changes in levels of Th cytokines on the ocular surface have been measured in dry eye and the biological effects of these cytokines have been documented in experimental culture and mouse model systems. The Th2 cytokine IL-13 has a homeostatic role in promoting goblet cell differentiation. In contrast, The Th1 cytokine IFN-γ antagonizes IL-13 and promotes apoptosis and squamous metaplasia of the ocular surface epithelia. The Th17 cytokine, IL-17 promotes corneal epithelial barrier disruption. The ocular surface epithelium expresses receptors to all of these Th cytokines. Therapies that maintain normal IL-13 signaling, or suppress IFN-γ and IL-17 have potential for treating the ocular surface disease of dry eye.
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Affiliation(s)
- Stephen C Pflugfelder
- Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, 6565 Fannin NC205, Houston, TX 77030, USA.
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Yoon KC. Topical biological agents targeting cytokines for the treatment of dry eye disease. World J Ophthalmol 2013; 3:16-19. [DOI: 10.5318/wjo.v3.i2.16] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2013] [Revised: 07/26/2013] [Accepted: 08/06/2013] [Indexed: 02/06/2023] Open
Abstract
Because inflammation plays a key role in the pathogenesis of dry eye disease and Sjögren’s syndrome, topical anti-inflammatory agents such as corticosteroids and cyclosporine A have been used to treat inflammation of the ocular surface and lacrimal gland. Systemic biological agents that target specific immune molecules or cells such as tumor necrosis factor (TNF)-α, interferone-α, interleukin (IL)-1, IL-6, or B cells have been used in an attempt to treat Sjögren’s syndrome. However, the efficacy of systemic biological agents, other than B-cell targeting agents, has not yet been confirmed in Sjögren’s syndrome. Several studies have recently evaluated the efficacy of topical administration of biological agents targeting cytokines in the treatment of dry eye disease. Topical blockade of IL-1 by using IL-1 receptor antagonist could ameliorate clinical signs and inflammation of experimental dry eye. Using a mouse model of desiccating stress-induced dry eye, we have demonstrated that topical application of a TNF-α blocking agent, infliximab, could improve tear production and ocular surface irregularity, decrease inflammatory cytokines and Th-1 CD4+ cells on the ocular surface, and increase goblet cell density in the conjunctiva. Although controversy still remains, the use of topical biological agents targeting inflammatory cytokines may be a promising therapy for human dry eye disease.
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Ding C, Li L, Su YC, Xiang RL, Cong X, Yu HK, Li SL, Wu LL, Yu GY. Adiponectin increases secretion of rat submandibular gland via adiponectin receptors-mediated AMPK signaling. PLoS One 2013; 8:e63878. [PMID: 23667684 PMCID: PMC3646765 DOI: 10.1371/journal.pone.0063878] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 04/10/2013] [Indexed: 01/16/2023] Open
Abstract
Adiponectin and adiponectin receptors (AdipoR1/2) are expressed in various tissues and are involved in the regulation of multiple functions such as energy metabolism and inflammatory responses. However, the effect of adiponectin and AdipoRs in submandibular glands has not been fully evaluated. In the present study, we found that mRNA and protein of both adiponectin and AdipoR1/2 were expressed in rat submandibular glands and in the SMG-C6 cell line, as evidenced by RT-PCR and Western blot analysis. Immunofluorescence staining showed that adiponectin was diffused in the cytoplasm, while AdipoR1/2 was concentrated in the membrane of acinar cells. Saliva flow was significantly increased by full length adiponectin (fAd) or globular adiponectin (gAd) perfusion in isolated rat submandibular glands. 5-Aminoimidazole-4-carboxamide-1-4-ribofuranoside (AICAR), an adenosine monophosphate activated protein kinase (AMPK) activator, also increased saliva secretion. fAd, gAd, and AICAR all increased the average width of apical tight junctions in perfused submandibular glands, and decreased transepithelial electrical resistance (TER) in SMG-C6 cells, suggesting that adiponectin promoted secretion by modulating paracellular permeability. fAd and gAd increased p-AMPK levels, while AraA, an AMPK antagonist, abolished fAd- and gAd-induced changes in secretion, tight junction ultrastructure, and TER. Moreover, both AdipoR1 and AdipoR2 were required for fAd- or gAd-induced p-AMPK and TER responses, suggesting from their inhibition following AdipoR1 or AdipoR2 knockdown, and co-knockdown of AdipoRs by RNA interference. Our results suggest that adiponectin functions as a promoter of salivary secretion in rat submandibular glands via activation of AdipoRs, AMPK, and paracellular permeability.
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Affiliation(s)
- Chong Ding
- Center for Salivary Gland Diseases and Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
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Role of adipokines in atherosclerosis: interferences with cardiovascular complications in rheumatic diseases. Mediators Inflamm 2012; 2012:125458. [PMID: 22910888 PMCID: PMC3403095 DOI: 10.1155/2012/125458] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Accepted: 06/19/2012] [Indexed: 01/08/2023] Open
Abstract
Patients with rheumatic diseases have an increased risk of mortality by cardiovascular events. In fact, several rheumatic diseases such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis are associated with a higher prevalence of cardiovascular diseases (CVDs). Although traditional cardiovascular risk factors have been involved in the pathogenesis of cardiovascular diseases in rheumatic patients, these alterations do not completely explain the enhanced cardiovascular risk in this population. Obesity and its pathologic alteration of fat mass and dysfunction, due to an altered pattern of secretion of proinflammatory adipokines, could be one of the links between cardiovascular and rheumatic diseases. Indeed, the incidence of CVDs is augmented in obese individuals with rheumatic disorders. Thus, in this paper we explore in detail the relationships among adipokines, rheumatic diseases, and cardiovascular complications by giving to the reader a holistic vision and several suggestions for future perspectives and potential clinical implications.
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Kajiya M, Ichimonji I, Min C, Zhu T, Jin JO, Yu Q, Almazrooa SA, Cha S, Kawai T. Muscarinic type 3 receptor induces cytoprotective signaling in salivary gland cells through epidermal growth factor receptor transactivation. Mol Pharmacol 2012; 82:115-24. [PMID: 22511543 PMCID: PMC3382834 DOI: 10.1124/mol.111.077354] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 04/17/2012] [Indexed: 01/28/2023] Open
Abstract
Muscarinic type 3 receptor (M3R) plays a pivotal role in the induction of glandular fluid secretions. Although M3R is often the target of autoantibodies in Sjögren's syndrome (SjS), chemical agonists for M3R are clinically used to stimulate saliva secretion in patients with SjS. Aside from its activity in promoting glandular fluid secretion, however, it is unclear whether activation of M3R is related to other biological events in SjS. This study aimed to investigate the cytoprotective effect of chemical agonist-mediated M3R activation on apoptosis induced in human salivary gland (HSG) cells. Carbachol (CCh), a muscarinic receptor-specific agonist, abrogated tumor necrosis factor α/interferon γ-induced apoptosis through pathways involving caspase 3/7, but its cytoprotective effect was decreased by a M3R antagonist, a mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) inhibitor, a phosphatidylinositol 3-kinase/Akt inhibitor, or an epidermal growth factor receptor (EGFR) inhibitor. Ligation of M3R with CCh transactivated EGFR and phosphorylated ERK and Akt, the downstream targets of EGFR. Inhibition of intracellular calcium release or protein kinase C δ, both of which are involved in the cell signaling of M3R-mediated fluid secretion, did not affect CCh-induced ERK or Akt phosphorylation. CCh stimulated Src phosphorylation and binding to EGFR. A Src inhibitor attenuated the CCh/M3R-induced cytoprotective effect and EGFR transactivation cascades. Overall, these results indicated that CCh/M3R induced transactivation of EGFR through Src activation leading to ERK and Akt phosphorylation, which in turn suppressed caspase 3/7-mediated apoptotic signals in HSG cells. This study, for the first time, proposes that CCh-mediated M3R activation can promote not only fluid secretion but also survival of salivary gland cells in the inflammatory context of SjS.
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Affiliation(s)
- Mikihito Kajiya
- Department of Immunology, Forsyth Institute, Cambridge, Massachusetts 02142, USA
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Krysiak R, Handzlik-Orlik G, Okopien B. The role of adipokines in connective tissue diseases. Eur J Nutr 2012; 51:513-28. [PMID: 22584415 PMCID: PMC3397228 DOI: 10.1007/s00394-012-0370-0] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Accepted: 04/26/2012] [Indexed: 12/14/2022]
Abstract
Objective To discuss the relationship between adipokines and connective tissue diseases, by putting special emphasis on the potential role of leptin, adiponectin, resistin, and other adipose tissue products in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus and on possible application of adipokine-targeted therapy in the treatment of these disorders with emphasis on the recent findings. Methods PubMed literature search complemented by review of bibliographies listed in identified articles. Results Most of the data presented by different research groups showed changed levels of leptin, adiponectin, and resistin and occasionally also other adpokines in rheumatoid arthritis and systemic lupus erythematosus. The relationship between the remaining connective tissue diseases and adipokines is less documented. Conclusions Plasma levels of adipokines might tell us too little about their role in connective tissue disorders, whereas adipokine effects on synovial tissues might differ from their known metabolic or cardiovascular effects, which implies that some re-appraisal of adipokines role may need to take place. It still remains obscure whether the observed disturbances in various adipokine systems in subjects with connective tissue diseases contribute to their development or only reflect the presence or activity of inflammatory process, which itself is induced by other pro-inflammatory factors.
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Affiliation(s)
- Robert Krysiak
- Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752, Katowice, Poland
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Tremblay M, Loucif Y, Methot J, Brisson D, Gaudet D. Salivary pH as a marker of plasma adiponectin concentrations in Women. Diabetol Metab Syndr 2012; 4:4. [PMID: 22304893 PMCID: PMC3306272 DOI: 10.1186/1758-5996-4-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Accepted: 02/03/2012] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Plasma adiponectin is a significant correlate of the pro-inflammatory cardiometabolic risk profile associated with obesity and type 2 diabetes. Salivary pH is influenced by several cardiometabolic risk components such as inflammation, oxidation and numerous oral and systemic health modulators, including the menopausal status. This study aimed to assess the association between plasma adiponectin concentrations and salivary pH in women according to the menopausal status. METHOD Unstimulated saliva collection was performed in 151 Caucasian women of French-Canadian origin (53 premenopausal women (PMW) and 98 menopausal women (MW)). Student's t test, ANOVA and linear regression models were used to assess the association between plasma adiponectin concentrations and salivary pH. RESULTS Plasma adiponectin levels increased as a function of salivary pH in the whole sample and among MW (r = 0.29 and r = 0.36, p < 0.001). The proportion of the variance of plasma adiponectin levels explained by the salivary pH (R2) was 10.8% (p < 0.001). Plasma adiponectin levels progressively increased across salivary pH quartiles (p = 0.005). CONCLUSIONS These results suggest that salivary pH is a significant correlate of plasma adiponectin levels in women. With the increasing prevalence of type 2 diabetes and obesity, new technologies should be developed to more easily monitor health status, disease onset and progression. Salivary pH, a simple, inexpensive and non-invasive measure, could be a very promising avenue.
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Affiliation(s)
- Monique Tremblay
- Department of Medicine, Université de Montréal, ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, QC, Canada
| | - Yacine Loucif
- Department of Medicine, Université de Montréal, ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, QC, Canada
| | - Julie Methot
- Department of Medicine, Université de Montréal, ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, QC, Canada
| | - Diane Brisson
- Department of Medicine, Université de Montréal, ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, QC, Canada
| | - Daniel Gaudet
- Department of Medicine, Université de Montréal, ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, QC, Canada
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Szyszko EA, Brokstad KA, Oijordsbakken G, Jonsson MV, Jonsson R, Skarstein K. Salivary glands of primary Sjögren's syndrome patients express factors vital for plasma cell survival. Arthritis Res Ther 2011; 13:R2. [PMID: 21214903 PMCID: PMC3241347 DOI: 10.1186/ar3220] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2010] [Revised: 11/19/2010] [Accepted: 01/07/2011] [Indexed: 01/15/2023] Open
Abstract
INTRODUCTION The presence of circulating Ro/SSA and La/SSB autoantibodies has become an important marker in the classification criteria for primary Sjögren's syndrome (pSS). Plasma cells producing these autoantibodies are mainly high affinity plasma cells originating from germinal centre reactions. When exposed to the right microenvironment these autoimmune plasma cells become long-lived and resistant to immunosuppressive treatment. Since autoimmune plasma cells have been detected in the salivary glands of SS patients, we wanted to investigate if the glandular microenvironment is suitable for plasma cell survival and if glandular residing plasma cells are the long-lived plasma cell subset. METHODS Single, double and triple immunohistochemistry as well as immunofluorescence staining was performed on minor salivary gland tissue retrieved from pSS, chronically inflamed and normal subjects. RESULTS We detected significant numbers of CD138+, non-proliferating, Bcl-2 expressing plasma cells in the salivary glands of pSS patients with high focus score (FS). Furthermore, we demonstrated that CXCL12 and interleukin (IL)-6 survival factors were highly expressed in pSS salivary gland epithelium and by focal mononuclear infiltrating cells. Notably, adipocytes when present in the salivary gland tissue were an important source of CXCL12. We clearly demonstrate that plasma cells are localised in close proximity to CXCL12 and IL-6 expressing cells and thus that the environment of salivary glands with high FS provide factors vital for plasma cell survival. CONCLUSIONS Plasma cells residing in the salivary glands of pSS patients with high FS showed phenotypic characteristics of the long-lived plasma cell subtype. Furthermore, the pSS salivary gland microenvironment provided niches rich in factors vital for plasma cell survival.
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Affiliation(s)
- Ewa A Szyszko
- Broegelmann Research Laboratory, The Gade Institute, University of Bergen, The Laboratory Building, Bergen N-5021, Norway.
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Zhu M, Flynt L, Ghosh S, Mellema M, Banerjee A, Williams E, Panettieri RA, Shore SA. Anti-inflammatory effects of thiazolidinediones in human airway smooth muscle cells. Am J Respir Cell Mol Biol 2010; 45:111-9. [PMID: 20870897 DOI: 10.1165/rcmb.2009-0445oc] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Airway smooth muscle (ASM) cells have been reported to contribute to the inflammation of asthma. Because the thiazolidinediones (TZDs) exert anti-inflammatory effects, we examined the effects of troglitazone and rosiglitazone on the release of inflammatory moieties from cultured human ASM cells. Troglitazone dose-dependently reduced the IL-1β-induced release of IL-6 and vascular endothelial growth factor, the TNF-α-induced release of eotaxin and regulated on activation, normal T expressed and secreted (RANTES), and the IL-4-induced release of eotaxin. Rosiglitazone also inhibited the TNF-α-stimulated release of RANTES. Although TZDs are known to activate peroxisome proliferator-activated receptor-γ (PPARγ), these anti-inflammatory effects were not affected by a specific PPARγ inhibitor (GW 9662) or by the knockdown of PPARγ using short hairpin RNA. Troglitazone and rosiglitazone each caused the activation of adenosine monophosphate-activated protein kinase (AMPK), as detected by Western blotting using a phospho-AMPK antibody. The anti-inflammatory effects of TZDs were largely mimicked by the AMPK activators, 5-amino-4-imidazolecarboxamide ribose (AICAR) and metformin. However, the AMPK inhibitors, Ara A and Compound C, were not effective in preventing the anti-inflammatory effects of troglitazone or rosiglitzone, suggesting that the effects of these TZDs are likely not mediated through the activation of AMPK. These data indicate that TZDs inhibit the release of a variety of inflammatory mediators from human ASM cells, suggesting that they may be useful in the treatment of asthma, and the data also indicate that the effects of TZDs are not mediated by PPARγ or AMPK.
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Affiliation(s)
- Ming Zhu
- Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115-6021, USA
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