Th17-Gene Expression Profile in Patients with Chronic Venous Disease and Venous Ulcers: Genetic Modulations and Preliminary Clinical Evidence
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Procedures
2.2. Collection of Blood Samples
2.3. RNA Extraction and qRT-PCR
2.4. Immunoblotting
2.5. Statistical Analysis
3. Results
3.1. Baseline Characteristics
3.2. Th17 Gene Expression Evaluation and Protein Expression Validation
3.3. Correlation Study
3.4. ROC and Multivariable Logistic Regression Analysis
4. Discussion
5. Study Limitations
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Serra, R.; Grande, R.; Butrico, L.; Fugetto, F.; de Franciscis, S. Epidemiology, Diagnosis and Treatment of Chronic Venous Disease: A Systematic Review. Chirurgia 2016, 29, 34–45. [Google Scholar]
- Green, J.; Jester, R.; McKinley, R.; Pooler, A. The Impact of Chronic Venous Leg Ulcers: A Systematic Review. J. Wound Care 2014, 23, 601–612. [Google Scholar] [CrossRef] [PubMed]
- Serra, R.; Andreucci, M.; de Caridi, G.; Massara, M.; Mastroroberto, P.; de Franciscis, S. Functional Chronic Venous Disease: A Systematic Review. Phlebology 2017, 32, 588–592. [Google Scholar] [CrossRef] [PubMed]
- Serra, R.; Ssempijja, L.; Provenzano, M.; Andreucci, M. Genetic Biomarkers in Chronic Venous Disease. Biomark. Med. 2020, 14, 75–80. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Serra, R.; Buffone, G.; de Franciscis, A.; Mastrangelo, D.; Molinari, V.; Montemurro, R.; de Franciscis, S. A Genetic Study of Chronic Venous Insufficiency. Ann. Vasc. Surg. 2012, 26, 636–642. [Google Scholar] [CrossRef]
- Sándor, T. Pathomechanism of Chronic Venous Insufficiency and Leg Ulcer. Acta Physiol. Hung. 2004, 91, 131–145. [Google Scholar] [CrossRef]
- Smith, P.D. Update on Chronic-Venous-Insufficiency-Induced Inflammatory Processes. Angiology 2001, 52 (Suppl. 1), S35–S42. [Google Scholar] [CrossRef]
- Kim, J.S.; Jordan, M.S. Diversity of IL-17-Producing T Lymphocytes. Cell. Mol. Life Sci. 2013, 70, 2271–2290. [Google Scholar] [CrossRef] [Green Version]
- Moseley, T.A.; Haudenschild, D.R.; Rose, L.; Reddi, A.H. Interleukin-17 Family and IL-17 Receptors. Cytokine Growth Factor Rev. 2003, 14, 155–174. [Google Scholar] [CrossRef]
- Zhang, Z.; Zhang, K.; Zhang, M.; Zhang, X.; Zhang, R. Parthenolide Suppresses T Helper 17 and Alleviates Experimental Autoimmune Encephalomyelitis. Front. Immunol. 2022, 13. [Google Scholar] [CrossRef]
- Monteleone, I.; Sarra, M.; Pallone, F.; Monteleone, G. Th17-Related Cytokines in Inflammatory Bowel Diseases: Friends or Foes? Curr. Mol. Med. 2012, 12, 592–597. [Google Scholar] [CrossRef] [PubMed]
- Planas, D.; Routy, J.P.; Ancuta, P. New Th17-Specific Therapeutic Strategies for HIV Remission. Curr. Opin. HIV AIDS 2019, 14, 85–92. [Google Scholar] [CrossRef] [PubMed]
- Renault, C.; Veyrenche, N.; Mennechet, F.; Bedin, A.S.; Routy, J.P.; van de Perre, P.; Reynes, J.; Tuaillon, E. Th17 CD4+ T-Cell as a Preferential Target for HIV Reservoirs. Front. Immunol. 2022, 13. [Google Scholar] [CrossRef] [PubMed]
- Marques, H.S.; de Brito, B.B.; da Silva, F.A.F.; Santos, M.L.C.; de Souza, J.C.B.; Correia, T.M.L.; Lopes, L.W.; Neres, N.S.M.; Dórea, R.S.D.M.; Dantas, A.C.S.; et al. Relationship between Th17 Immune Response and Cancer. World J. Clin. Oncol. 2021, 12, 845–867. [Google Scholar] [CrossRef]
- Martonik, D.; Parfieniuk-Kowerda, A.; Rogalska, A.; Flisiak, R. The Role of Th17 Response in COVID-19. Cells 2021, 10, 1550. [Google Scholar] [CrossRef]
- Monteleone, I.; Pallone, F.; Monteleone, G. Th17-Related Cytokines: New Players in the Control of Chronic Intestinal Inflammation. BMC Med. 2011, 9, 122. [Google Scholar] [CrossRef] [Green Version]
- Wu, C.; Chen, Z.; Xiao, S.; Thalhamer, T.; Madi, A.; Han, T.; Kuchroo, V. SGK1 Governs the Reciprocal Development of Th17 and Regulatory T Cells. Cell Rep. 2018, 22, 653–665. [Google Scholar] [CrossRef] [Green Version]
- Kleinewietfeld, M.; Manzel, A.; Titze, J.; Kvakan, H.; Yosef, N.; Linker, R.A.; Muller, D.N.; Hafler, D.A. Sodium Chloride Drives Autoimmune Disease by the Induction of Pathogenic TH17 Cells. Nature 2013, 496, 518–522. [Google Scholar] [CrossRef]
- Wu, C.; Yosef, N.; Thalhamer, T.; Zhu, C.; Xiao, S.; Kishi, Y.; Regev, A.; Kuchroo, V.K. Induction of Pathogenic TH17 Cells by Inducible Salt-Sensing Kinase SGK1. Nature 2013, 496, 513–517. [Google Scholar] [CrossRef] [Green Version]
- Spagnuolo, R.; Dattilo, V.; D’Antona, L.; Cosco, C.; Tallerico, R.; Ventura, V.; Conforti, F.; Camastra, C.; Mancina, R.M.; Catalogna, G.; et al. Deregulation of SGK1 in Ulcerative Colitis: A Paradoxical Relationship between Immune Cells and Colonic Epithelial Cells. Inflamm. Bowel Dis. 2018, 24, 1967–1977. [Google Scholar] [CrossRef]
- Lurie, F.; Passman, M.; Meisner, M.; Dalsing, M.; Masuda, E.; Welch, H.; Bush, R.L.; Blebea, J.; Carpentier, P.H.; de Maeseneer, M.; et al. The 2020 Update of the CEAP Classification System and Reporting Standards. J. Vasc. Surg. Venous Lymphat. Disord. 2020, 8, 342–352. [Google Scholar] [CrossRef] [PubMed]
- Edlinger, M.; van Smeden, M.; Alber, H.F.; Wanitschek, M.; van Calster, B. Risk Prediction Models for Discrete Ordinal Outcomes: Calibration and the Impact of the Proportional Odds Assumption. Stat. Med. 2022, 41, 1334–1360. [Google Scholar] [CrossRef] [PubMed]
- Grzela, T.; Bialoszewska, A. Genetic Risk Factors of Chronic Venous Leg Ulceration: Can Molecular Screening Aid in the Prevention of Chronic Venous Insufficiency Complications? Mol. Med. Rep. 2010, 3, 205–211. [Google Scholar] [CrossRef] [Green Version]
- Raffetto, J.D. Inflammation in Chronic Venous Ulcers. Phlebology 2013, 28 (Suppl. 1), 61–67. [Google Scholar] [CrossRef] [PubMed]
- Caprioli, F.; Pallone, F.; Monteleone, G. Th17 Immune Response in IBD: A New Pathogenic Mechanism. J. Crohn’s Colitis 2008, 2, 291–295. [Google Scholar] [CrossRef] [PubMed]
- Perrotti, N.; He, R.A.; Phillips, S.A.; Haft, C.R.; Taylor, S.I. Activation of Serum- and Glucocorticoid-Induced Protein Kinase (Sgk) by Cyclic AMP and Insulin. J. Biol. Chem. 2001, 276, 9406–9412. [Google Scholar] [CrossRef] [Green Version]
- Talarico, C.; Dattilo, V.; D’Antona, L.; Menniti, M.; Bianco, C.; Ortuso, F.; Alcaro, S.; Schenone, S.; Perrotti, N.; Amato, R. SGK1, the New Player in the Game of Resistance: Chemo-Radio Molecular Target and Strategy for Inhibition. Cell. Physiol. Biochem. 2016, 39, 1863–1876. [Google Scholar] [CrossRef]
- Dattilo, V.; D’Antona, L.; Talarico, C.; Capula, M.; Catalogna, G.; Iuliano, R.; Schenone, S.; Roperto, S.; Bianco, C.; Perrotti, N.; et al. SGK1 Affects RAN/RANBP1/RANGAP1 via SP1 to Play a Critical Role in Pre-MiRNA Nuclear Export: A New Route of Epigenomic Regulation. Sci. Rep. 2017, 7, 45361. [Google Scholar] [CrossRef] [Green Version]
- Catalogna, G.; Moraca, F.; D’Antona, L.; Dattilo, V.; Perrotti, G.; Lupia, A.; Costa, G.; Ortuso, F.; Iuliano, R.; Trapasso, F.; et al. Review about the Multi-Target Profile of Resveratrol and Its Implication in the SGK1 Inhibition. Eur. J. Med. Chem. 2019, 183, 111675. [Google Scholar] [CrossRef]
- Catalogna, G.; Talarico, C.; Dattilo, V.; Gangemi, V.; Calabria, F.; D’Antona, L.; Schenone, S.; Musumeci, F.; Bianco, C.; Perrotti, N.; et al. The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells. Cell. Physiol. Biochem. 2017, 43, 108–119. [Google Scholar] [CrossRef] [Green Version]
- D’Antona, L.; Dattilo, V.; Catalogna, G.; Scumaci, D.; Fiumara, C.V.; Musumeci, F.; Perrotti, G.; Schenone, S.; Tallerico, R.; Spoleti, C.B.; et al. In Preclinical Model of Ovarian Cancer, the SGK1 Inhibitor SI113 Counteracts the Development of Paclitaxel Resistance and Restores Drug Sensitivity. Transl. Oncol. 2019, 12, 1045–1055. [Google Scholar] [CrossRef]
- Ma, X.; Zhang, L.; Song, J.; Nguyen, E.; Lee, R.S.; Rodgers, S.J.; Li, F.; Huang, C.; Schittenhelm, R.B.; Chan, H.; et al. Characterization of the Src-Regulated Kinome Identifies SGK1 as a Key Mediator of Src-Induced Transformation. Nat. Commun. 2019, 10, 296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dattilo, V.; Amato, R.; Perrotti, N.; Gennarelli, M. The Emerging Role of SGK1 (Serum- and Glucocorticoid-Regulated Kinase 1) in Major Depressive Disorder: Hypothesis and Mechanisms. Front. Genet. 2020, 11. [Google Scholar] [CrossRef] [PubMed]
- Amato, R.; Scumaci, D.; D’Antona, L.; Iuliano, R.; Menniti, M.; di Sanzo, M.; Faniello, M.C.; Colao, E.; Malatesta, P.; Zingone, A.; et al. Sgk1 Enhances RANBP1 Transcript Levels and Decreases Taxol Sensitivity in RKO Colon Carcinoma Cells. Oncogene 2013, 32, 4572–4578. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Abbruzzese, C.; Catalogna, G.; Gallo, E.; di Martino, S.; Mileo, A.M.; Carosi, M.; Dattilo, V.; Schenone, S.; Musumeci, F.; Lavia, P.; et al. The Small Molecule SI113 Synergizes with Mitotic Spindle Poisons in Arresting the Growth of Human Glioblastoma Multiforme. Oncotarget 2017, 8, 110743–110755. [Google Scholar] [CrossRef] [Green Version]
- Talarico, C.; Dattilo, V.; D’Antona, L.; Barone, A.; Amodio, N.; Belviso, S.; Musumeci, F.; Abbruzzese, C.; Bianco, C.; Trapasso, F.; et al. SI113, a SGK1 Inhibitor, Potentiates the Effects of Radiotherapy, Modulates the Response to Oxidative Stress and Induces Cytotoxic Autophagy in Human Glioblastoma Multiforme Cells. Oncotarget 2016, 7, 15868–15884. [Google Scholar] [CrossRef] [Green Version]
- Abbruzzese, C.; Matteoni, S.; Persico, M.; Ascione, B.; Schenone, S.; Musumeci, F.; Amato, R.; Perrotti, N.; Matarrese, P.; Paggi, M.G. The Small Molecule SI113 Hinders Epithelial-to-mesenchymal Transition and Subverts Cytoskeletal Organization in Human Cancer Cells. J. Cell. Physiol. 2019, 234, 22529–22542. [Google Scholar] [CrossRef]
- Conza, D.; Mirra, P.; Calì, G.; Tortora, T.; Insabato, L.; Fiory, F.; Schenone, S.; Amato, R.; Beguinot, F.; Perrotti, N.; et al. The SGK1 Inhibitor SI113 Induces Autophagy, Apoptosis, and Endoplasmic Reticulum Stress in Endometrial Cancer Cells. J. Cell. Physiol. 2017, 232, 3735–3743. [Google Scholar] [CrossRef]
- Deng, J.; Yu, X.Q.; Wang, P.H. Inflammasome Activation and Th17 Responses. Mol. Immunol. 2019, 107, 142–164. [Google Scholar] [CrossRef]
- Monteleone, I.; Marafini, I.; Dinallo, V.; di Fusco, D.; Troncone, E.; Zorzi, F.; Laudisi, F.; Monteleone, G. Sodium Chloride–Enriched Diet Enhanced Inflammatory Cytokine Production and Exacerbated Experimental Colitis in Mice. J. Crohn’s Colitis 2017, 11, 237–245. [Google Scholar] [CrossRef] [Green Version]
- Nicola, S.; Fornero, M.; Fusaro, E.; Peroni, C.; Priora, M.; Rolla, G.; Bucca, C.; Brussino, L.; Pirozzi, C.J. Th1-and Th17-Related Cytokines in Venous and Arterial Blood of Sclerodermic Patients with and without Digital Ulcers. BioMed Res. Int. 2019, 2019, 7908793. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Binger, K.J.; Linker, R.A.; Muller, D.N.; Kleinewietfeld, M. Sodium Chloride, SGK1, and Th17 Activation. Pflug. Arch. Eur. J. Physiol. 2015, 467, 543–550. [Google Scholar] [CrossRef] [PubMed]
- von Vietinghoff, S.; Ley, K. Interleukin 17 in Vascular Inflammation. Cytokine Growth Factor Rev. 2010, 21, 463–469. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Overall (N = 23) | Control (N = 8) | CVD (C2–C4) (N = 8) | Venous Ulcer (C6) (N = 7) | p | |
---|---|---|---|---|---|
Age, years | 55.9 ± 16.9 | 51.4 ± 16.3 | 52.5 ± 11.6 | 65.0 ± 21.1 | 0.046 |
Male gender, % | 47.8 | 50.0 | 25.0 | 71.4 | 0.197 |
Body Mass Index, Kg/m2 | 28.3 ± 6.2 | 28.4 ± 4.9 | 27.5 ± 8.0 | 29.0 ± 6.2 | 0.905 |
Smoking habit, % | 8.7 | 12.5 | 12.5 | 0 | 0.619 |
History of Cardiovascular D. % | 4.4 | 0 | 0 | 14.3 | 0.303 |
Hypertension, % | 26.1 | 12.5 | 25.0 | 42.9 | 0.408 |
Systolic BP, mmHg | 129.2 ± 12.2 | 120.0 ± 6.0 | 130.3 ± 11.1 | 138.6 ± 11.1 | 0.006 |
Diastolic BP, mmHg | 81.8 ± 6.8 | 81.9 ± 7.0 | 83.4 ± 5.2 | 80.0 ± 8.9 | 0.655 |
Salt consumption | 0.409 | ||||
Low | 17.4 | 37.5 | 12.5 | 0 | |
High | 21.7 | 12.5 | 25.0 | 28.6 | |
Extreme | 60.9 | 50.0 | 62.5 | 71.4 | |
Antihypertensive drugs, % | 26.1 | 12.5 | 25.0 | 42.9 | 0.408 |
Statins, % | 13.0 | 12.5 | 12.5 | 14.3 | 0.993 |
Diuretics, % | 8.7 | 0 | 12.5 | 14.3 | 0.553 |
Antiplatelet agents, % | 30.4 | 25.0 | 25.0 | 42.9 | 0.693 |
Anticoagulant agents, % | 4.4 | 0 | 12.5 | 0 | 0.375 |
Characteristics | OR (95% CI) | p |
---|---|---|
IL23R | 1.70 (1.08–2.69) | 0.022 |
IL17 | 1.12 (1.06–1.30) | 0.041 |
RORG | 1.49 (1.23–2.47) | 0.005 |
RANBP1 | 2.27 (1.77–6.70) | 0.016 |
SGK1 | 1.17 (0.88–1.56) | 0.292 |
TGF-β | 0.87 (0.57–1.31) | 0.492 |
FOXO1 | 2.58 (0.82–8.06) | 0.104 |
Characteristics | OR (95% CI) | p |
---|---|---|
IL23R | 1.91 (1.04–3.52) | 0.037 |
IL17 | 5.18 (1.26–11.32) | 0.023 |
RORG | 1.66 (0.95–2.88) | 0.053 |
RANBP1 | 1.31 (0.38–4.45) | 0.667 |
SGK1 | 2.44 (1.05–5.68) | 0.038 |
TGF-β | 1.78 (0.97–3.25) | 0.062 |
FOXO1 | 2.24 (0.65–5.12) | 0.231 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Amato, R.; Dattilo, V.; Brescia, C.; D’Antona, L.; Iuliano, R.; Trapasso, F.; Perrotti, N.; Costa, D.; Ielapi, N.; Aiello, F.; et al. Th17-Gene Expression Profile in Patients with Chronic Venous Disease and Venous Ulcers: Genetic Modulations and Preliminary Clinical Evidence. Biomolecules 2022, 12, 902. https://doi.org/10.3390/biom12070902
Amato R, Dattilo V, Brescia C, D’Antona L, Iuliano R, Trapasso F, Perrotti N, Costa D, Ielapi N, Aiello F, et al. Th17-Gene Expression Profile in Patients with Chronic Venous Disease and Venous Ulcers: Genetic Modulations and Preliminary Clinical Evidence. Biomolecules. 2022; 12(7):902. https://doi.org/10.3390/biom12070902
Chicago/Turabian StyleAmato, Rosario, Vincenzo Dattilo, Carolina Brescia, Lucia D’Antona, Rodolfo Iuliano, Francesco Trapasso, Nicola Perrotti, Davide Costa, Nicola Ielapi, Francesco Aiello, and et al. 2022. "Th17-Gene Expression Profile in Patients with Chronic Venous Disease and Venous Ulcers: Genetic Modulations and Preliminary Clinical Evidence" Biomolecules 12, no. 7: 902. https://doi.org/10.3390/biom12070902