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Wu W, Tong H, Li Y, Cui J. Diabetes mellitus, metformin's target gene AMPK, and inflammatory bowel disease: A Mendelian randomization study. Medicine (Baltimore) 2025; 104:e41532. [PMID: 39960958 PMCID: PMC11835072 DOI: 10.1097/md.0000000000041532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 01/27/2025] [Indexed: 02/20/2025] Open
Abstract
The causal relationship between inflammatory bowel disease (IBD) and diabetes mellitus remains unclear. The aim of this study was to delve into this association and investigate the correlation between AMP-activated protein kinase (AMPK), a target gene of metformin, and the risk of developing IBD. Researchers conducted a bidirectional two-sample Mendelian randomization analysis to examine causal relationships between IBD, including ulcerative colitis and Crohn disease (CD), and diabetes mellitus, encompassing both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Additionally, this study utilized AMPK-related variants associated with HbA1c (%) as instrumental variables for the metformin target gene AMPK to further investigate their association with the risk of IBD. The inverse variance weighted method was used as the primary analytical approach. Mendelian randomization analysis revealed a suggestive association between IBD and T1DM (P = .024). CD was associated with an increased risk of T1DM (P = .011). In the reverse analysis, T1DM also increased the risk of IBD (P = .043). No causal relationship was found between IBD and T2DM in either the forward or reverse analyses. In addition, this study did not find any significant effect of AMPK on IBD. In conclusion, this study suggests a bidirectional association between IBD and T1DM, in which CD may increase the risk of T1DM. However, no causal relationship was found between IBD and T2DM. Furthermore, our findings revealed that the metformin's target gene AMPK had no significant effect on the onset of IBD.
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Affiliation(s)
- Wei Wu
- Department of Geriatrics, Chun’an First People’s Hospital (Chun’an Branch of Zhejiang Provincial People’s Hospital), Hangzhou, Zhejiang Province, China
| | - Huomu Tong
- Department of Endocrinology, Chun’an First People’s Hospital (Chun’an Branch of Zhejiang Provincial People’s Hospital), Hangzhou, Zhejiang Province, China
| | - Yunsheng Li
- Department of Geriatrics, Chun’an First People’s Hospital (Chun’an Branch of Zhejiang Provincial People’s Hospital), Hangzhou, Zhejiang Province, China
| | - Jia Cui
- Department of Endocrinology, Chun’an First People’s Hospital (Chun’an Branch of Zhejiang Provincial People’s Hospital), Hangzhou, Zhejiang Province, China
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Xie W, Jiang H, Chen Y, Yu Z, Song Y, Zhang H, Li S, Han S, Liu N. Relationship between type 1 diabetes and autoimmune diseases in european populations: A two-sample Mendelian randomization study. Front Genet 2024; 15:1335839. [PMID: 39350769 PMCID: PMC11439667 DOI: 10.3389/fgene.2024.1335839] [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: 01/15/2024] [Accepted: 08/22/2024] [Indexed: 10/04/2024] Open
Abstract
Background Previous studies have suggested an association between Type 1 diabetes (T1D) and autoimmune diseases (AIDs), but the causal relationship remains unclear. Therefore, this study utilizes publicly available Genome-Wide Association Studies (GWAS) databases and employs a two-sample Mendelian Randomization (MR) approach to explore the causal relationships between T1D and systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). Methods Summary GWAS data for T1D, SLE, RA, and IBD were downloaded from open GWAS databases and the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). We employed a series of methods to select instrumental variables closely related to T1D. To enhance the reliability of our conclusions, we applied multiple robust analytical methods, with the inverse variance weighted (IVW) method as the primary approach. Validation and meta-analysis were conducted using the FinnGen consortium. Additionally, we assessed heterogeneity, pleiotropy, and sensitivity to ensure the robustness of our conclusions. Results A potential causal association was found between T1D and SLE (OR = 1.37, 95% CI = 1.26 - 1.49, P < 0.001), which was further confirmed by meta-analysis. Similarly, a potential causal association was found between T1D and RA (OR = 1.32, 95% CI = 1.17 - 1.50, P < 0.001), and this was also confirmed by meta-analysis. Although the association between T1D and IBD showed P < 0.05, the leave-one-out test did not pass, and further meta-analysis indicated no significant statistical association between them. Conclusion Our study reveals the relationships between T1D and three clinically common autoimmune diseases (SLE, RA, and IBD). This research supplements previous studies and provides a reference for future clinical work.
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Affiliation(s)
- Weidong Xie
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Haojie Jiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yao Chen
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Graduate School, Zhejiang University, Hangzhou, China
| | - Zhaojie Yu
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Yaoyu Song
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Huanhao Zhang
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Sen Li
- School of Basic Medicine, Wenzhou Medical University, Wenzhou, China
| | - Shaoliang Han
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Naxin Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Tong KK, Yu YF, Yang XY, Wu JY, Yu R, Tan CC. Does type 1 diabetes serve as a protective factor against inflammatory bowel disease: A Mendelian randomization study. World J Diabetes 2024; 15:1551-1561. [PMID: 39099830 PMCID: PMC11292335 DOI: 10.4239/wjd.v15.i7.1551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 05/02/2024] [Accepted: 05/28/2024] [Indexed: 07/08/2024] Open
Abstract
BACKGROUND The impact of type 1 diabetes (T1D) on inflammatory bowel disease (IBD) remains unclear. AIM To analyze the causal relationship between T1D and IBD using Mendelian ran-domization (MR). METHODS Single nucleotide polymorphisms were sourced from FinnGen for T1D, IBD, ulcerative colitis (UC) and Crohn's disease (CD). Inverse variance-weighted, MR-Egger, and weighted median tests were used to assess exposure-outcome causality. The MR-Egger intercept was used to assess horizontal pleiotropy. Co-chran's Q and leave-one-out method were used to analyze heterogeneity and sensitivity, respectively. RESULTS Our MR analysis indicated that T1D was associated with a reduced risk of IBD [odds ratio (OR): 0.959; 95% confidence interval (CI): 0.938-0.980; P < 0.001] and UC (OR: 0.960; 95%CI: 0.929-0.992; P = 0.015), with no significant association observed in terms of CD risk (OR: 0.966; 95%CI: 0.913-1.022; P = 0.227). The MR-Egger intercept showed no horizontal pleiotropy (P > 0.05). Cochran's Q and leave-one-out sensitivity analyses showed that the results were not heterogeneous (P > 0.05) and were robust. CONCLUSION This MR analysis suggests that T1D serves as a potential protective factor against IBD and UC but is independent of CD.
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Affiliation(s)
- Ke-Ke Tong
- The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan Province, China
| | - Yun-Feng Yu
- The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan Province, China
| | - Xin-Yu Yang
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Jing-Yi Wu
- The Third Hospital, Zhejiang Chinese Medical University, Hangzhou 310005, Zhejiang Province, China
| | - Rong Yu
- The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan Province, China
| | - Chuan-Chuan Tan
- The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan Province, China
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Li S, Luo Z, Su S, Wen L, Xian G, Zhao J, Xu X, Xu D, Zeng Q. Targeted inhibition of PTPN22 is a novel approach to alleviate osteogenic responses in aortic valve interstitial cells and aortic valve lesions in mice. BMC Med 2023; 21:252. [PMID: 37443055 PMCID: PMC10347738 DOI: 10.1186/s12916-023-02888-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 05/02/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND Calcific aortic valve disease (CAVD) is the most prevalent valvular disease and has high morbidity and mortality. CAVD is characterized by complex pathophysiological processes, including inflammation-induced osteoblastic differentiation in aortic valve interstitial cells (AVICs). Novel anti-CAVD agents are urgently needed. Protein tyrosine phosphatase nonreceptor type 22 (PTPN22), an intracellular nonreceptor-like protein tyrosine phosphatase, is involved in several chronic inflammatory diseases, including rheumatoid arthritis and diabetes. However, it is unclear whether PTPN22 is involved in the pathogenesis of CAVD. METHODS We obtained the aortic valve tissue from human and cultured AVICs from aortic valve. We established CAVD mice model by wire injury. Transcriptome sequencing, western bolt, qPCR, and immunofluorescence were performed to elucidate the molecular mechanisms. RESULTS Here, we determined that PTPN22 expression was upregulated in calcific aortic valve tissue, AVICs treated with osteogenic medium, and a mouse model of CAVD. In vitro, overexpression of PTPN22 induced osteogenic responses, whereas siRNA-mediated PTPN22 knockdown abolished osteogenic responses and mitochondrial stress in the presence of osteogenic medium. In vivo, PTPN22 ablation ameliorated aortic valve lesions in a wire injury-induced CAVD mouse model, validating the pathogenic role of PTPN22 in CAVD. Additionally, we discovered a novel compound, 13-hydroxypiericidin A 10-O-α-D-glucose (1 → 6)-β-D-glucoside (S18), in a marine-derived Streptomyces strain that bound to PTPN22 with high affinity and acted as a novel inhibitor. Incubation with S18 suppressed osteogenic responses and mitochondrial stress in human AVICs induced by osteogenic medium. In mice with aortic valve injury, S18 administration markedly alleviated aortic valve lesions. CONCLUSION PTPN22 plays an essential role in the progression of CAVD, and inhibition of PTPN22 with S18 is a novel option for the further development of potent anti-CAVD drugs. Therapeutic inhibition of PTPN22 retards aortic valve calcification through modulating mitochondrial dysfunction in AVICs.
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Affiliation(s)
- Shunyi Li
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Southern Medical University, Guangzhou, 510515, China
| | - Zichao Luo
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Southern Medical University, Guangzhou, 510515, China
| | - Shuwen Su
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Southern Medical University, Guangzhou, 510515, China
| | - Liming Wen
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Southern Medical University, Guangzhou, 510515, China
| | - Gaopeng Xian
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Southern Medical University, Guangzhou, 510515, China
| | - Jing Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Xingbo Xu
- Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August-University, Göttingen, Germany
| | - Dingli Xu
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Southern Medical University, Guangzhou, 510515, China.
| | - Qingchun Zeng
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Southern Medical University, Guangzhou, 510515, China.
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Román-Fernández IV, Machado-Contreras JR, Muñoz-Valle JF, Cruz A, Salazar-Camarena DC, Palafox-Sánchez CA. Altered PTPN22 and IL10 mRNA Expression Is Associated with Disease Activity and Renal Involvement in Systemic Lupus Erythematosus. Diagnostics (Basel) 2022; 12:diagnostics12112859. [PMID: 36428917 PMCID: PMC9689646 DOI: 10.3390/diagnostics12112859] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/06/2022] [Accepted: 11/15/2022] [Indexed: 11/19/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with very heterogeneous clinical behavior between affected individuals. Therefore, the search for biomarkers clinically useful for the diagnosis, prognosis, and monitoring of the disease is necessary. Here, we determined the association between PTPN22, IL10, OAS2, and CD70 mRNA expression with the clinical characteristics and with the serum levels of IL-10, IFN-γ, and IL-17 in SLE patients. Forty patients with SLE and 34 control subjects (CS) were included, mRNA expression was determined by real-time qPCR and cytokine levels were quantified by a multiplex bead-based immunoassay. Compared to CS, SLE patients showed increased IL10 mRNA and high IL-10 and IL-17 serum levels; in contrast, PTPN22 mRNA and IFN-γ were decreased. PTPN22 and IL10 gene expression was negatively correlated with Mex-SLEDAI score and were notably downregulated in SLE patients with lupus nephritis. Interestingly, SLE patients with renal damage were the ones with the lowest levels of PTPN22 and IL10 mRNA and the highest SLEDAI scores. No associations were observed for OAS2 and CD70 mRNA and IL-10, IL-17, and IFN-γ. In conclusion, we suggest that the assessment of IL10 and PTPN22 mRNA could be useful for monitoring disease activity in SLE patients showing renal involvement.
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Affiliation(s)
- Ilce Valeria Román-Fernández
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Jesús René Machado-Contreras
- Laboratorio de Inmunología, Facultad de Medicina, Universidad Autónoma de Baja California, Mexicali 21000, Mexico
| | - José Francisco Muñoz-Valle
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Alvaro Cruz
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Diana Celeste Salazar-Camarena
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Claudia Azucena Palafox-Sánchez
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
- Departamento de Reumatología, Hospital General de Occidente, Secretaría de Salud, Guadalajara 45170, Mexico
- Correspondence:
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6
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Schwarzfischer M, Niechcial A, Handler K, Morsy Y, Wawrzyniak M, Laimbacher AS, Atrott K, Manzini R, Baebler K, Hering L, Katkeviciutė E, Häfliger J, Lang S, Keller ME, Woodtli J, Eisenbeiss L, Kraemer T, Schraner EM, Wiesendanger M, Zeissig S, Rogler G, Moor AE, Scharl M, Spalinger MR. TiO 2 nanoparticles abrogate the protective effect of the Crohn's disease-associated variation within the PTPN22 gene locus. Gut 2022; 72:1101-1114. [PMID: 36191962 DOI: 10.1136/gutjnl-2021-325911] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 09/04/2022] [Indexed: 12/08/2022]
Abstract
OBJECTIVE Inflammatory bowel disease (IBD) is a multifactorial condition driven by genetic and environmental risk factors. A genetic variation in the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene has been associated with autoimmune disorders while protecting from the IBD subtype Crohn's disease. Mice expressing the murine orthologous PTPN22-R619W variant are protected from intestinal inflammation in the model of acute dextran sodium sulfate (DSS)-induced colitis. We previously identified food-grade titanium dioxide (TiO2, E171) as a neglected IBD risk factor. Here, we investigate the interplay of the PTPN22 variant and TiO2-mediated effects during IBD pathogenesis. DESIGN Acute DSS colitis was induced in wild-type and PTPN22 variant mice (PTPN22-R619W) and animals were treated with TiO2 nanoparticles during colitis induction. Disease-triggering mechanisms were investigated using bulk and single-cell RNA sequencing. RESULTS In mice, administration of TiO2 nanoparticles abrogated the protective effect of the variant, rendering PTPN22-R619W mice susceptible to DSS colitis. In early disease, cytotoxic CD8+ T-cells were found to be reduced in the lamina propria of PTPN22-R619W mice, an effect reversed by TiO2 administration. Normalisation of T-cell populations correlated with increased Ifng expression and, at a later stage of disease, the promoted prevalence of proinflammatory macrophages that triggered severe intestinal inflammation. CONCLUSION Our findings indicate that the consumption of TiO2 nanoparticles might have adverse effects on the gastrointestinal health of individuals carrying the PTPN22 variant. This demonstrates that environmental factors interact with genetic risk variants and can reverse a protective mechanism into a disease-promoting effect.
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Affiliation(s)
- Marlene Schwarzfischer
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Anna Niechcial
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Kristina Handler
- Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland
| | - Yasser Morsy
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Marcin Wawrzyniak
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Andrea S Laimbacher
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Kirstin Atrott
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Roberto Manzini
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Katharina Baebler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Larissa Hering
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Egle Katkeviciutė
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Janine Häfliger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Silvia Lang
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Maja E Keller
- Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland
| | - Jérôme Woodtli
- Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland
| | - Lisa Eisenbeiss
- Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland
| | - Thomas Kraemer
- Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland
| | - Elisabeth M Schraner
- Institutes of Veterinary Anatomy and Virology, University of Zurich, Zurich, Switzerland
| | - Mahesa Wiesendanger
- Institutes of Veterinary Anatomy and Virology, University of Zurich, Zurich, Switzerland
| | - Sebastian Zeissig
- Center for Regenerative Therapies Dresden (CRTD), Technische Universität (TU) Dresden, and Department of Medicine I, University Medical Center Dresden, Dresden, Germany
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Andreas E Moor
- Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Marianne R Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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Tizaoui K, Shin JI, Jeong GH, Yang JW, Park S, Kim JH, Hwang SY, Park SJ, Koyanagi A, Smith L. Genetic Polymorphism of PTPN22 in Autoimmune Diseases: A Comprehensive Review. Medicina (B Aires) 2022; 58:medicina58081034. [PMID: 36013501 PMCID: PMC9415475 DOI: 10.3390/medicina58081034] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/23/2022] [Accepted: 07/26/2022] [Indexed: 12/04/2022] Open
Abstract
It is known that the etiology and clinical outcomes of autoimmune diseases are associated with a combination of genetic and environmental factors. In the case of the genetic factor, the SNPs of the PTPN22 gene have shown strong associations with several diseases. The recent exploding numbers of genetic studies have made it possible to find these associations rapidly, and a variety of autoimmune diseases were found to be associated with PTPN22 polymorphisms. Proteins encoded by PTPN22 play a key role in the adaptative and immune systems by regulating both T and B cells. Gene variants, particularly SNPs, have been shown to significantly disrupt several immune functions. In this review, we summarize the mechanism of how PTPN22 and its genetic variants are involved in the pathophysiology of autoimmune diseases. In addition, we sum up the findings of studies reporting the genetic association of PTPN22 with different types of diseases, including type 1 diabetes mellitus, systemic lupus erythematosus, juvenile idiopathic arthritis, and several other diseases. By understanding these findings comprehensively, we can explain the complex etiology of autoimmunity and help to determine the criteria of disease diagnosis and prognosis, as well as medication developments.
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Affiliation(s)
- Kalthoum Tizaoui
- Department of Basic Sciences, Division of Histology and Immunology, Faculty of Medicine Tunis, Tunis El Manar University, Tunis 2092, Tunisia;
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Korea;
| | - Gwang Hun Jeong
- College of Medicine, Gyeongsang National University, Jinju 52727, Korea;
| | - Jae Won Yang
- Department of Nephrology, Yonsei University Wonju College of Medicine, Wonju 26426, Korea;
| | - Seoyeon Park
- Yonsei University College of Medicine, Seoul 06273, Korea; (S.P.); (S.Y.H.)
| | - Ji Hong Kim
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Korea;
- Correspondence: ; Tel.: +82-2-2019-3352; Fax: +82-2-3461-9473
| | - Soo Young Hwang
- Yonsei University College of Medicine, Seoul 06273, Korea; (S.P.); (S.Y.H.)
| | - Se Jin Park
- Department of Pediatrics, Eulji University School of Medicine, Daejeon 35233, Korea;
| | - Ai Koyanagi
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, Dr. Antoni Pujadas, 42, Sant Boi de Llobregat, 08830 Barcelona, Spain;
- ICREA, Pg. Lluis Companys 23, 08010 Barcelona, Spain
| | - Lee Smith
- Centre for Health Performance and Wellbeing, Anglia Ruskin University, Cambridge CB1 1PT, UK;
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Hu M, Chen Z, Liao Y, Wu J, Zheng D, Zhang H. Clinical value of the expression levels of protein tyrosine phosphatase non-receptor type 22.6 mRNA in peripheral blood mononuclear cells in Crohn's disease. Clin Exp Immunol 2022; 209:311-315. [PMID: 35751647 PMCID: PMC9521657 DOI: 10.1093/cei/uxac061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/16/2022] [Accepted: 06/24/2022] [Indexed: 01/23/2023] Open
Abstract
OBJECTIVE To explore the relationship between the expression levels of protein tyrosine phosphatase non-receptor type (PTPN) 22.6 mRNA in peripheral blood mononuclear cells (PBMCs) and the disease activity as well as clinical characteristics in Crohn's disease (CD) patients. METHODS A total of 480 subjects were enrolled. Data were collected including baseline information, expression levels of PTPN22.6 mRNA in PBMCs for all subjects, C-reactive protein (CRP) levels in serum, clinical characteristics, and disease activity for all patients. Expression levels of PTPN22.6 mRNA in PBMCs, CRP levels in serum, clinical characteristics according to Montreal Classification [8], and Crohn's disease activity index (CDAI) were the primary observation outcomes. RESULTS The expression levels of PTPN22.6 mRNA (P = 0.032) in PBMCs and serum CRP levels (P < 0.001) were significantly higher in active CD patients than in inactive CD patients (P = 0.032). Correlation analysis showed that there was a positive correlation between expression levels of PTPN22.6 mRNA and CDAI value (r = 0.512, P = 0.003), as well as expression levels of PTPN22.6 mRNA and CRP levels in the CD group (r = 0.456, P = 0.006). There were significantly higher expression levels of PTPN22.6 mRNA in PBMCs in patients with structuring behavior than that in patients with non-stricturing and non-penetrating (NSNP) behaviors (P = 0.018) and penetrating behaviors (P = 0.024). CONCLUSIONS The expression levels of PTPN22.6 mRNA can be used as an indicator to help predict CD diagnosis, disease activity, serum CRP level, and behavior type of CD disease.
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Affiliation(s)
| | | | - Yusheng Liao
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory for Molecular Diagnosis of Hubei Province, Wuhan, People’s Republic of China
| | - Jie Wu
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory for Molecular Diagnosis of Hubei Province, Wuhan, People’s Republic of China
| | - Dan Zheng
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory for Molecular Diagnosis of Hubei Province, Wuhan, People’s Republic of China
| | - Heng Zhang
- Correspondence: Heng Zhang, Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology Sheng Li Street 26, Wuhan 430014, Hubei Province, People’s Republic of China.
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Millrine D, Jenkins RH, Hughes STO, Jones SA. Making sense of IL-6 signalling cues in pathophysiology. FEBS Lett 2022; 596:567-588. [PMID: 34618359 PMCID: PMC9673051 DOI: 10.1002/1873-3468.14201] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 12/15/2022]
Abstract
Unravelling the molecular mechanisms that account for functional pleiotropy is a major challenge for researchers in cytokine biology. Cytokine-receptor cross-reactivity and shared signalling pathways are considered primary drivers of cytokine pleiotropy. However, reports epitomized by studies of Jak-STAT cytokine signalling identify interesting biochemical and epigenetic determinants of transcription factor regulation that affect the delivery of signal-dependent cytokine responses. Here, a regulatory interplay between STAT transcription factors and their convergence to specific genomic enhancers support the fine-tuning of cytokine responses controlling host immunity, functional identity, and tissue homeostasis and repair. In this review, we provide an overview of the signalling networks that shape the way cells sense and interpret cytokine cues. With an emphasis on the biology of interleukin-6, we highlight the importance of these mechanisms to both physiological processes and pathophysiological outcomes.
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Affiliation(s)
- David Millrine
- Division of Infection & ImmunitySchool of MedicineCardiff UniversityUK
- Systems Immunity University Research InstituteCardiff UniversityUK
- Present address:
Medical Research Council Protein Phosphorylation and Ubiquitylation UnitSir James Black CentreSchool of Life SciencesUniversity of Dundee3rd FloorDundeeUK
| | - Robert H. Jenkins
- Division of Infection & ImmunitySchool of MedicineCardiff UniversityUK
- Systems Immunity University Research InstituteCardiff UniversityUK
| | - Stuart T. O. Hughes
- Division of Infection & ImmunitySchool of MedicineCardiff UniversityUK
- Systems Immunity University Research InstituteCardiff UniversityUK
| | - Simon A. Jones
- Division of Infection & ImmunitySchool of MedicineCardiff UniversityUK
- Systems Immunity University Research InstituteCardiff UniversityUK
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10
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Spalinger MR, Crawford M, Bobardt SD, Li J, Sayoc-Becerra A, Santos AN, Shawki A, Chatterjee P, Nair MG, McCole DF. Loss of protein tyrosine phosphatase non-receptor type 2 reduces IL-4-driven alternative macrophage activation. Mucosal Immunol 2022; 15:74-83. [PMID: 34420044 PMCID: PMC8732276 DOI: 10.1038/s41385-021-00441-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 07/06/2021] [Accepted: 07/31/2021] [Indexed: 02/04/2023]
Abstract
Macrophages are a heterogeneous population of innate immune cells that are often divided into two major subsets: classically activated, typically pro-inflammatory (M1) macrophages that mediate host defense, and alternatively activated, tolerance-inducing (M2) macrophages that exert homeostatic and tissue-regenerative functions. Disturbed macrophage function/differentiation results either in inadequate, excessive immune activation or in a failure to induce efficient protective immune responses against pathogens. Loss-of-function variants in protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with chronic inflammatory disorders, but the effect of macrophage-intrinsic PTPN2 loss is still poorly understood. Here we report that PTPN2-deficient macrophages fail to acquire an alternatively activated/M2 phenotype. This was the consequence of reduced IL-6 receptor expression and a failure to induce IL-4 receptor in response to IL-6, resulting in an inability to respond to the key M2-inducing cytokine IL-4. Ultimately, failure to adequately respond to IL-6 and IL-4 resulted in increased levels of M1 macrophage marker expression in vitro and exacerbated lung inflammation upon infection with Nippostrongylus brasiliensis in vivo. These results demonstrate that PTPN2 loss interferes with the ability of macrophages to adequately respond to inflammatory stimuli and might explain the increased susceptibility of PTPN2 loss-of-function carriers to developing inflammatory diseases.
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Affiliation(s)
- Marianne R Spalinger
- Division of Biomedical Sciences, University of California Riverside, Riverside, CA, USA.
| | - Meli'sa Crawford
- Division of Biomedical Sciences, University of California Riverside, Riverside, CA, USA
| | - Sarah D Bobardt
- Division of Biomedical Sciences, University of California Riverside, Riverside, CA, USA
| | - Jiang Li
- Division of Biomedical Sciences, University of California Riverside, Riverside, CA, USA
| | - Anica Sayoc-Becerra
- Division of Biomedical Sciences, University of California Riverside, Riverside, CA, USA
| | - Alina N Santos
- Division of Biomedical Sciences, University of California Riverside, Riverside, CA, USA
| | - Ali Shawki
- Division of Biomedical Sciences, University of California Riverside, Riverside, CA, USA
| | - Pritha Chatterjee
- Division of Biomedical Sciences, University of California Riverside, Riverside, CA, USA
| | - Meera G Nair
- Division of Biomedical Sciences, University of California Riverside, Riverside, CA, USA
| | - Declan F McCole
- Division of Biomedical Sciences, University of California Riverside, Riverside, CA, USA
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11
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The Immunogenetics of Systemic Sclerosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1367:259-298. [DOI: 10.1007/978-3-030-92616-8_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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12
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Lin SN, Mao R, Qian C, Bettenworth D, Wang J, Li J, Bruining D, Jairath V, Feagan B, Chen M, Rieder F. Development of Anti-fibrotic Therapy in Stricturing Crohn's Disease: Lessons from Randomized Trials in Other Fibrotic Diseases. Physiol Rev 2021; 102:605-652. [PMID: 34569264 DOI: 10.1152/physrev.00005.2021] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Intestinal fibrosis is considered an inevitable complication of Crohn's disease (CD) that results in symptoms of obstruction and stricture formation. Endoscopic or surgical treatment is required to treat the majority of patients. Progress in the management of stricturing CD is hampered by the lack of effective anti-fibrotic therapy; however, this situation is likely to change because of recent advances in other fibrotic diseases of the lung, liver and skin. In this review, we summarized data from randomized controlled trials (RCT) of anti-fibrotic therapies in these conditions. Multiple compounds have been tested for the anti-fibrotic effects in other organs. According to their mechanisms, they were categorized into growth factor modulators, inflammation modulators, 5-hydroxy-3-methylgultaryl-coenzyme A (HMG-CoA) reductase inhibitors, intracellular enzymes and kinases, renin-angiotensin system (RAS) modulators and others. From our review of the results from the clinical trials and discussion of their implications in the gastrointestinal tract, we have identified several molecular candidates that could serve as potential therapies for intestinal fibrosis in CD.
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Affiliation(s)
- Si-Nan Lin
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States.,Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, United States
| | - Ren Mao
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States.,Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, United States
| | - Chenchen Qian
- Department of Internal Medicine, UPMC Pinnacle, Harrisburg, Pennsylvania, United States
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| | - Jie Wang
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States.,Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, United States.,Henan Key Laboratory of Immunology and Targeted Drug, Xinxiang Medical University, Xinxiang, Henan Province, China
| | - Jiannan Li
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States.,Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, United States
| | - David Bruining
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
| | - Vipul Jairath
- Alimentiv Inc., London, ON, Canada.,Department of Medicine, Western University, London, ON, Canada.,Department of Biostatistics and Epidemiology, Western University, London, ON, Canada
| | - Brian Feagan
- Alimentiv Inc., London, ON, Canada.,Department of Medicine, Western University, London, ON, Canada.,Department of Biostatistics and Epidemiology, Western University, London, ON, Canada
| | - Minhu Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | | | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States.,Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, United States
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13
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Shaw AM, Qasem A, Naser SA. Modulation of PTPN2/22 Function by Spermidine in CRISPR-Cas9-Edited T-Cells Associated with Crohn's Disease and Rheumatoid Arthritis. Int J Mol Sci 2021; 22:8883. [PMID: 34445589 PMCID: PMC8396355 DOI: 10.3390/ijms22168883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/12/2021] [Accepted: 08/17/2021] [Indexed: 12/02/2022] Open
Abstract
Crohn's Disease (CD) and Rheumatoid Arthritis (RA) share some single nucleotide polymorphisms (SNPs) in protein tyrosine phosphatase non-receptor types 2 and 22 (PTPN2/22). Recently, we reported that clinical samples from CD and RA patients associated with PTPN2:rs478582 or PTPN22:rs2476601 genotypes were linked to overactive immune response and exacerbation of inflammation. Here, we investigated in vitro the effects of these SNPs in Jurkat T-cells using CRISPR-Cas9. All cells were evaluated for PTPN22/22 loss of function and effects on cell response. We measured gene expression via RT-qPCR and cytokines by ELISA. We also measured cell proliferation using a BrdU labeling proliferation ELISA, and T-cell activation using CD-25 fluorescent immunostaining. In PTPN2 SNP-edited cells, PTPN2 expression decreased by 3.2-fold, and proliferation increased by 10.2-fold compared to control. Likewise, expression of PTPN22 decreased by 2.4-fold and proliferation increased by 8.4-fold in PTPN22 SNP-edited cells. IFN-γ and TNF-α secretions increased in both edited cell lines. CD25 expression (cell activation) was 80.32% in PTPN2 SNP-edited cells and 85.82% in PTPN22 SNP-edited cells compared to 70.48% in unedited Jurkat T-cells. Treatment of PTPN2 and PTPN22-edited cells with a maximum 20 μM spermidine restored PTPN2/22 expression and cell response including cell proliferation, activation, and cytokines secretion. Most importantly, the effect of spermidine on edited cells restored normal expression and secretion of IFN-γ and TNF-α. The data clearly demonstrated that edited SNPs in PTPN2 or PTPN22 were associated with reduced gene expression, which resulted in an increase in cell proliferation and activation and overactive immune response. The data validated our earlier observations in CD and RA clinical samples. Surprisingly, spermidine restored PTPN2/22 expression in edited Jurkat T-cells and the consequent beneficial effect on cell response and inflammation. The study supports the use of polyamines dietary supplements for management of CD and in RA patients.
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MESH Headings
- Arthritis, Rheumatoid/genetics
- CRISPR-Cas Systems
- Crohn Disease/genetics
- Gene Expression Regulation, Leukemic/drug effects
- Genetic Predisposition to Disease
- Humans
- Jurkat Cells
- Leukemia, T-Cell/drug therapy
- Leukemia, T-Cell/genetics
- Leukemia, T-Cell/pathology
- Lymphocyte Activation
- Polymorphism, Single Nucleotide
- Protein Tyrosine Phosphatase, Non-Receptor Type 2/antagonists & inhibitors
- Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/antagonists & inhibitors
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/metabolism
- Spermidine/pharmacology
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Affiliation(s)
| | | | - Saleh A. Naser
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4110 Libra Drive, Orlando, FL 32816, USA; (A.M.S.); (A.Q.)
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14
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Ho WJ, Croessmann S, Lin J, Phyo ZH, Charmsaz S, Danilova L, Mohan AA, Gross NE, Chen F, Dong J, Aggarwal D, Bai Y, Wang J, He J, Leatherman JM, Yarchoan M, Armstrong TD, Zaidi N, Fertig EJ, Denny JC, Park BH, Zhang ZY, Jaffee EM. Systemic inhibition of PTPN22 augments anticancer immunity. J Clin Invest 2021; 131:146950. [PMID: 34283806 PMCID: PMC8409589 DOI: 10.1172/jci146950] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 07/16/2021] [Indexed: 12/19/2022] Open
Abstract
Both epidemiologic and cellular studies in the context of autoimmune diseases have established that protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a key regulator of T cell receptor (TCR) signaling. However, its mechanism of action in tumors and its translatability as a target for cancer immunotherapy have not been established. Here we show that a germline variant of PTPN22, rs2476601, portended a lower likelihood of cancer in patients. PTPN22 expression was also associated with markers of immune regulation in multiple cancer types. In mice, lack of PTPN22 augmented antitumor activity with greater infiltration and activation of macrophages, natural killer (NK) cells, and T cells. Notably, we generated a novel small molecule inhibitor of PTPN22, named L-1, that phenocopied the antitumor effects seen in genotypic PTPN22 knockout. PTPN22 inhibition promoted activation of CD8+ T cells and macrophage subpopulations toward MHC-II expressing M1-like phenotypes, both of which were necessary for successful antitumor efficacy. Increased PD1-PDL1 axis in the setting of PTPN22 inhibition could be further leveraged with PD1 inhibition to augment antitumor effects. Similarly, cancer patients with the rs2476601 variant responded significantly better to checkpoint inhibitor immunotherapy. Our findings suggest that PTPN22 is a druggable systemic target for cancer immunotherapy.
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Affiliation(s)
- Won Jin Ho
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Sarah Croessmann
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jianping Lin
- Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA
| | - Zaw H. Phyo
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Soren Charmsaz
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Ludmila Danilova
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Aditya A. Mohan
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Nicole E. Gross
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Fangluo Chen
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Jiajun Dong
- Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA
| | - Devesh Aggarwal
- Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA
| | - Yunpeng Bai
- Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA
| | - Janey Wang
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jing He
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - James M. Leatherman
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Mark Yarchoan
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Todd D. Armstrong
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Neeha Zaidi
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Elana J. Fertig
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Joshua C. Denny
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- All of Us Research Program and National Human Genome Research Institute, NIH, Bethesda, Maryland, USA
| | - Ben H. Park
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA
| | - Elizabeth M. Jaffee
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
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15
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Tizaoui K, Terrazzino S, Cargnin S, Lee KH, Gauckler P, Li H, Shin JI, Kronbichler A. The role of PTPN22 in the pathogenesis of autoimmune diseases: A comprehensive review. Semin Arthritis Rheum 2021; 51:513-522. [PMID: 33866147 DOI: 10.1016/j.semarthrit.2021.03.004] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 01/16/2021] [Accepted: 03/03/2021] [Indexed: 02/07/2023]
Abstract
The incidence of autoimmune diseases is increasing worldwide, thus stimulating studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors. Genetic association studies have shown the PTPN22 gene as a shared genetic risk factor with implications in multiple autoimmune disorders. By encoding a protein tyrosine phosphatase expressed by the majority of cells belonging to the innate and adaptive immune systems, the PTPN22 gene may have a fundamental role in the development of immune dysfunction. PTPN22 polymorphisms are associated with rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and many other autoimmune conditions. In this review, we discuss the progress in our understanding of how PTPN22 impacts autoimmunity in both humans and animal models. In addition, we highlight the pathogenic significance of the PTPN22 gene, with particular emphasis on its role in T and B cells, and its function in innate immune cells, such as monocytes, dendritic and natural killer cells. We focus particularly on the complexity of PTPN22 interplay with biological processes of the immune system. Findings highlight the importance of studying the function of disease-associated PTPN22 variants in different cell types and open new avenues of investigation with the potential to drive further insights into mechanisms of PTPN22. These new insights will reveal important clues to the molecular mechanisms of prevalent autoimmune diseases and propose new potential therapeutic targets.
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Affiliation(s)
- Kalthoum Tizaoui
- Department of Basic Sciences, Division of Histology and Immunology, Faculty of Medicine Tunis, Tunis El Manar University, Tunis 1068, Tunisia
| | - Salvatore Terrazzino
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Sarah Cargnin
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Philipp Gauckler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
| | - Han Li
- University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
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16
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Armitage LH, Wallet MA, Mathews CE. Influence of PTPN22 Allotypes on Innate and Adaptive Immune Function in Health and Disease. Front Immunol 2021; 12:636618. [PMID: 33717184 PMCID: PMC7946861 DOI: 10.3389/fimmu.2021.636618] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 01/18/2021] [Indexed: 01/18/2023] Open
Abstract
Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) regulates a panoply of leukocyte signaling pathways. A single nucleotide polymorphism (SNP) in PTPN22, rs2476601, is associated with increased risk of Type 1 Diabetes (T1D) and other autoimmune diseases. Over the past decade PTPN22 has been studied intensely in T cell receptor (TCR) and B cell receptor (BCR) signaling. However, the effect of the minor allele on PTPN22 function in TCR signaling is controversial with some reports concluding it has enhanced function and blunts TCR signaling and others reporting it has reduced function and increases TCR signaling. More recently, the core function of PTPN22 as well as functional derangements imparted by the autoimmunity-associated variant allele of PTPN22 have been examined in monocytes, macrophages, dendritic cells, and neutrophils. In this review we will discuss the known functions of PTPN22 in human cells, and we will elaborate on how autoimmunity-associated variants influence these functions across the panoply of immune cells that express PTPN22. Further, we consider currently unresolved questions that require clarification on the role of PTPN22 in immune cell function.
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Affiliation(s)
- Lucas H. Armitage
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, United States
| | - Mark A. Wallet
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, United States
- Immuno-Oncology at Century Therapeutics, LLC, Philadelphia, PA, United States
| | - Clayton E. Mathews
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, United States
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17
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Spalinger MR, Schwarzfischer M, Scharl M. The Role of Protein Tyrosine Phosphatases in Inflammasome Activation. Int J Mol Sci 2020; 21:E5481. [PMID: 32751912 PMCID: PMC7432435 DOI: 10.3390/ijms21155481] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 07/29/2020] [Accepted: 07/29/2020] [Indexed: 12/13/2022] Open
Abstract
Inflammasomes are multi-protein complexes that mediate the activation and secretion of the inflammatory cytokines IL-1β and IL-18. More than half a decade ago, it has been shown that the inflammasome adaptor molecule, ASC requires tyrosine phosphorylation to allow effective inflammasome assembly and sustained IL-1β/IL-18 release. This finding provided evidence that the tyrosine phosphorylation status of inflammasome components affects inflammasome assembly and that inflammasomes are subjected to regulation via kinases and phosphatases. In the subsequent years, it was reported that activation of the inflammasome receptor molecule, NLRP3, is modulated via tyrosine phosphorylation as well, and that NLRP3 de-phosphorylation at specific tyrosine residues was required for inflammasome assembly and sustained IL-1β/IL-18 release. These findings demonstrated the importance of tyrosine phosphorylation as a key modulator of inflammasome activity. Following these initial reports, additional work elucidated that the activity of several inflammasome components is dictated via their phosphorylation status. Particularly, the action of specific tyrosine kinases and phosphatases are of critical importance for the regulation of inflammasome assembly and activity. By summarizing the currently available literature on the interaction of tyrosine phosphatases with inflammasome components we here provide an overview how tyrosine phosphatases affect the activation status of inflammasomes.
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Affiliation(s)
- Marianne R. Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland; (M.S.); (M.S.)
| | - Marlene Schwarzfischer
- Department of Gastroenterology and Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland; (M.S.); (M.S.)
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland; (M.S.); (M.S.)
- Zurich Center for Integrative Human Physiology, University of Zurich, 8006 Zurich, Switzerland
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18
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Loss of PTPN22 abrogates the beneficial effect of cohousing-mediated fecal microbiota transfer in murine colitis. Mucosal Immunol 2019; 12:1336-1347. [PMID: 31501515 DOI: 10.1038/s41385-019-0201-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 08/13/2019] [Accepted: 08/19/2019] [Indexed: 02/07/2023]
Abstract
Fecal microbiota transfer (FMT) is a very efficient approach for the treatment of severe and recurring C. difficile infections. However, the beneficial effect of FMT in other disorders such as ulcerative colitis (UC) or Crohn's disease remains unclear. Furthermore, it is currently unknown how disease-associated genetic variants in donors or recipients influence the effect of FMT. We found that bacteria-transfer from wild-type (WT) donors via cohousing was efficient in inducing recovery from colitis in WT mice, but not in mice deficient in protein-tyrosine phosphatase non-receptor type 22 (PTPN22), a known risk gene for several chronic inflammatory diseases. Also cohousing of PTPN22-deficient mice with diseased WT mice failed to induce faster recovery. Our data indicate that the genetic background of the donor and the recipient influences the outcome of microbiota transfer, and offers a potential explanation why transfer of fecal microbes from some, but not all donors is efficient in UC patients.
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19
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Yahia-Cherbal H, Rybczynska M, Lovecchio D, Stephen T, Lescale C, Placek K, Larghero J, Rogge L, Bianchi E. NFAT primes the human RORC locus for RORγt expression in CD4 + T cells. Nat Commun 2019; 10:4698. [PMID: 31619674 PMCID: PMC6795897 DOI: 10.1038/s41467-019-12680-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 09/24/2019] [Indexed: 02/07/2023] Open
Abstract
T helper 17 (Th17) cells have crucial functions in mucosal immunity and the pathogenesis of several chronic inflammatory diseases. The lineage-specific transcription factor, RORγt, encoded by the RORC gene modulates Th17 polarization and function, as well as thymocyte development. Here we define several regulatory elements at the human RORC locus in thymocytes and peripheral CD4+ T lymphocytes, with CRISPR/Cas9-guided deletion of these genomic segments supporting their role in RORγt expression. Mechanistically, T cell receptor stimulation induces cyclosporine A-sensitive histone modifications and P300/CBP acetylase recruitment at these elements in activated CD4+ T cells. Meanwhile, NFAT proteins bind to these regulatory elements and activate RORγt transcription in cooperation with NF-kB. Our data thus demonstrate that NFAT specifically regulate RORγt expression by binding to the RORC locus and promoting its permissive conformation. The master transcription factor RORγt, encoded by the RORC gene, controls the polarization of CD4+ T cells expressing interleukin-17 (Th17). Here the authors describe several regulatory elements at the RORC locus that are recognized by NFAT and NFkB to induce a permissive epigenetic configuration of the RORC gene for RORγt expression and Th17 differentiation.
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Affiliation(s)
- Hanane Yahia-Cherbal
- Institut Pasteur, Immunoregulation Unit, Department of Immunology, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France
| | - Magda Rybczynska
- Institut Pasteur, Immunoregulation Unit, Department of Immunology, Paris, France.,Laboratoire Colloides et Matériaux Divisés, École supérieure de Physique et de Chimie industrielles, Paris, France
| | - Domenica Lovecchio
- Institut Pasteur, Immunoregulation Unit, Department of Immunology, Paris, France
| | - Tharshana Stephen
- Institut Pasteur, Unité de Technologie et Service Cytométrie et Biomarqueurs (UTechS CB), Centre de recherche translationnelle (CRT), Paris, France
| | - Chloé Lescale
- Institut Pasteur, Genome Integrity, Immunity and Cancer Unit, Equipe Labellisée Ligue Contre le Cancer, Department of Immunology, Department of Genomes and Genetics, Paris, France
| | - Katarzyna Placek
- Institut Pasteur, Immunoregulation Unit, Department of Immunology, Paris, France.,Immunology and Metabolism, LIMES Institute, University of Bonn, Bonn, Germany
| | - Jérome Larghero
- Assistance Publique-Hopitaux de Paris, Hôpital Saint-Louis, Cell Therapy Unit and Cord Blood Bank; CIC de Biothérapies, CBT501, Paris, France
| | - Lars Rogge
- Institut Pasteur, Immunoregulation Unit, Department of Immunology, Paris, France
| | - Elisabetta Bianchi
- Institut Pasteur, Immunoregulation Unit, Department of Immunology, Paris, France.
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20
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Spalinger MR, Schmidt TS, Schwarzfischer M, Hering L, Atrott K, Lang S, Gottier C, Geirnaert A, Lacroix C, Dai X, Rawlings DJ, Chan AC, von Mering C, Rogler G, Scharl M. Protein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent manner. J Clin Invest 2019; 129:2527-2541. [PMID: 31107248 DOI: 10.1172/jci123263] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 04/02/2019] [Indexed: 12/16/2022] Open
Abstract
The gut microbiota is crucial for our health, and well-balanced interactions between the host's immune system and the microbiota are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). A variant in protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with reduced risk of developing IBD, but promotes the onset of autoimmune disorders. While the role of PTPN22 in modulating molecular pathways involved in IBD pathogenesis is well studied, its impact on shaping the intestinal microbiota has not been addressed in depth. Here, we demonstrate that mice carrying the PTPN22 variant (619W mice) were protected from acute dextran sulfate sodium (DSS) colitis, but suffered from pronounced inflammation upon chronic DSS treatment. The basal microbiota composition was distinct between genotypes, and DSS-induced dysbiosis was milder in 619W mice than in WT littermates. Transfer of microbiota from 619W mice after the first DSS cycle into treatment-naive 619W mice promoted colitis, indicating that changes in microbial composition enhanced chronic colitis in those animals. This indicates that presence of the PTPN22 variant affects intestinal inflammation by modulating the host's response to the intestinal microbiota.
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Affiliation(s)
- Marianne R Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Thomas Sb Schmidt
- Institute of Molecular Life Science and Swiss Institute of Bioinformatics, University of Zurich, Zurich, Switzerland.,European Molecular Biology Laboratory, Heidelberg, Germany
| | - Marlene Schwarzfischer
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Larissa Hering
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Kirstin Atrott
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Silvia Lang
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Claudia Gottier
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Annelies Geirnaert
- Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Christophe Lacroix
- Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Xuezhi Dai
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA
| | - David J Rawlings
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA
| | - Andrew C Chan
- Research, Genentech Inc., South San Francisco, California, USA
| | - Christian von Mering
- Institute of Molecular Life Science and Swiss Institute of Bioinformatics, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.,Zurich Institute for Human Physiology, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.,Zurich Institute for Human Physiology, University of Zurich, Zurich, Switzerland
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21
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Ruiz-Noa Y, Hernández-Bello J, Llamas-Covarrubias MA, Palafox-Sánchez CA, Oregon-Romero E, Sánchez-Hernández PE, Ramírez-Dueñas MG, Parra-Rojas I, Muñoz-Valle JF. PTPN22 1858C>T polymorphism is associated with increased CD154 expression and higher CD4+ T cells percentage in rheumatoid arthritis patients. J Clin Lab Anal 2018; 33:e22710. [PMID: 30402903 DOI: 10.1002/jcla.22710] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 10/13/2018] [Accepted: 10/14/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND CD40 is a costimulatory molecule for B cells, and CD154 is a marker of CD4+ T cells activation. CD40-CD154 interaction promotes pro-inflammatory cytokines secretion and autoantibodies production. PTPN22 gene encodes LYP protein, an inhibitor of T- and B-cell activation. PTPN22 1858C>T polymorphism confers rheumatoid arthritis (RA) susceptibility. Hence, we evaluate the relationship between 1858C>T polymorphism with CD40 and CD154 expression and IFN-γ secretion in RA patients. METHODS PTPN22 1858C>T polymorphism was genotyped in 315 RA patients and 315 control subjects (CS) using PCR-RFLP method. Later, we selected only ten anti-CCP-positive RA patients, naïve to disease-modifying antirheumatic drugs and ten CS, all with known 1858C>T PTPN22 genotype. The CD40 and CD154 membrane expressions were determined by flow cytometry in peripheral B and T cells, correspondingly. RESULTS The B cells percentage and mCD40 expression were similar between RA and CS (P > 0.05) and we did not find an association between these variables and the 1858C>T polymorphism. The CD4+ T cells percentage was higher in RA patients than CS (P = 0.003), and in the RA group, the CD4+ T cells percentage and mCD154 expression were higher in the 1858 T allele carriers (P = 0.008 and P = 0.032, respectively). The IFN-γ levels were lower in RA patients carrying the PTPN22 risk allele (P = 0.032). CONCLUSION The PTPN22 1858 T risk allele is associated with increased CD4+ T cells percentage and high mCD154 expression in RA patients, which could favor the pro-inflammatory cytokine release and the establishment of the inflammatory response at the seropositive RA.
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Affiliation(s)
- Yeniley Ruiz-Noa
- Instituto de Investigación en Ciencias Biomédicas, CUCS, Universidad de Guadalajara, Guadalajara, México
| | - Jorge Hernández-Bello
- Instituto de Investigación en Ciencias Biomédicas, CUCS, Universidad de Guadalajara, Guadalajara, México
| | - Mara A Llamas-Covarrubias
- Instituto de Investigación en Ciencias Biomédicas, CUCS, Universidad de Guadalajara, Guadalajara, México
| | - Claudia A Palafox-Sánchez
- Instituto de Investigación en Ciencias Biomédicas, CUCS, Universidad de Guadalajara, Guadalajara, México
| | - Edith Oregon-Romero
- Instituto de Investigación en Ciencias Biomédicas, CUCS, Universidad de Guadalajara, Guadalajara, México
| | | | | | - Isela Parra-Rojas
- Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, México
| | - Jose Francisco Muñoz-Valle
- Instituto de Investigación en Ciencias Biomédicas, CUCS, Universidad de Guadalajara, Guadalajara, México
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22
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Yilmaz B, Spalinger MR, Biedermann L, Franc Y, Fournier N, Rossel JB, Juillerat P, Rogler G, Macpherson AJ, Scharl M. The presence of genetic risk variants within PTPN2 and PTPN22 is associated with intestinal microbiota alterations in Swiss IBD cohort patients. PLoS One 2018; 13:e0199664. [PMID: 29965986 PMCID: PMC6028086 DOI: 10.1371/journal.pone.0199664] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 06/12/2018] [Indexed: 01/03/2023] Open
Abstract
Background Genetic risk factors, intestinal microbiota and a dysregulated immune system contribute to the pathogenesis of inflammatory bowel disease (IBD). We have previously demonstrated that dysfunction of protein tyrosine phosphatase non-receptor type 2 (PTPN2) and PTPN22 contributes to alterations of intestinal microbiota and the onset of chronic intestinal inflammation in vivo. Here, we investigated the influence of PTPN2 and PTPN22 gene variants on intestinal microbiota composition in IBD patients. Methods Bacterial DNA from mucosa-associated samples of 75 CD and 57 UC patients were sequenced using 16S rRNA sequencing approach. Microbial analysis, including alpha diversity, beta diversity and taxonomical analysis by comparing to PTPN2 (rs1893217) and PTPN22 (rs2476601) genotypes was performed in QIIME, the phyloseq R package and MaAsLin pipeline. Results In PTPN2 variant UC patients, we detected an increase in relative abundance of unassigned genera from Clostridiales and Lachnospiraceae families and reduction of Roseburia when compared to PTPN2 wild-type (WT) patients. Ruminoccocus was increased in PTPN22 variant UC patients. In CD patients with severe disease course, Faecalibacterium, Bilophila, Coprococcus, unclassified Erysipelotrichaeceae, unassigned genera from Clostridiales and Ruminococcaceae families were reduced and Bacteroides were increased in PTPN2 WT carriers, while Faecalibacterium, Bilophila, Coprococcus, and Erysipelotrichaeceae were reduced in PTPN22 WT patients when compared to patients with mild disease. In UC patients with severe disease, relative abundance of Lachnobacterium was reduced in PTPN2 and PTPN22 WT patients, Dorea was increased in samples from PTPN22 WT carriers and an unassigned genus from Ruminococcaceae gen. was increased in patients with PTPN2 variant genotype. Conclusions We identified that IBD-associated genetic risk variants, disease severity and the interaction of these factors are related to significant alterations in intestinal microbiota composition of IBD patients.
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Affiliation(s)
- Bahtiyar Yilmaz
- Maurice Müller Laboratories, Department for Biomedical Research, University of Bern, Bern, Switzerland
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Marianne R. Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Luc Biedermann
- Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Yannick Franc
- Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne, Switzerland
| | - Nicolas Fournier
- Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne, Switzerland
| | - Jean-Benoit Rossel
- Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne, Switzerland
| | - Pascal Juillerat
- Maurice Müller Laboratories, Department for Biomedical Research, University of Bern, Bern, Switzerland
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Andrew J. Macpherson
- Maurice Müller Laboratories, Department for Biomedical Research, University of Bern, Bern, Switzerland
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
- * E-mail:
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23
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Sharp RC, Beg SA, Naser SA. Polymorphisms in Protein Tyrosine Phosphatase Non-receptor Type 2 and 22 (PTPN2/22) Are Linked to Hyper-Proliferative T-Cells and Susceptibility to Mycobacteria in Rheumatoid Arthritis. Front Cell Infect Microbiol 2018; 8:11. [PMID: 29423382 PMCID: PMC5788942 DOI: 10.3389/fcimb.2018.00011] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 01/09/2018] [Indexed: 12/19/2022] Open
Abstract
A shared genetic pre-disposition, chronic inflammation, and treatment with similar biologics between Rheumatoid arthritis (RA) and Crohn's disease (CD) have intrigued us to investigate whether the two disorders share trigger association or possible causation. We hypothesized earlier that Single Nucleotide Polymorphisms (SNPs) in the negative regulators Protein Tyrosine Phosphatase Non-receptor type 2 and 22 (PTPN2/22) lead to a dysregulated immune response, susceptibility to environmental triggers, and continued apoptosis as seen in chronic inflammation in RA and CD. To test the hypothesis, peripheral leukocytes samples from 132 consented subjects were genotyped for 9 SNPs in PTPN2/22 using TaqMan™ genotyping. The effect of the SNPs on PTPN2/22 and IFN-γ expression was determined using real time PCR. T-cell proliferation and response to phytohematoagglutonin (PHA) mitogen and mycobacterial antigens were determined by BrdU proliferation assay. Blood samples were also analyzed for the Mycobacterium avium subspecies paratuberculosis (MAP) IS900 gene by nPCR. Out of 9 SNPs examined, heterozygous (TC) or minor (CC) alleles of PTPN2:rs478582 occurred in 79% RA compared to 60% healthy controls (p-values ≤ 0.05; OR = 2.28). Similarly, heterozygous (GA) or minor (AA) alleles of PTPN22:rs2476601 occurred in 29% RA compared to 6% healthy controls (p-values ≤ 0.05; OR = 5.90). PTPN2/22 expression in RA was decreased by 1.2-fold compared to healthy controls. PTPN2:rs478582 upregulated IFN-γ in RA by 1.5-fold. Combined PTPN2:rs478582 and PTPN22:rs2476601 increased T-cell proliferation by 2.7-fold when treated with PHA. Surprisingly, MAP DNA was detected in 34% of RA samples compared to 8% healthy controls, (p-values ≤ 0.05, OR = 5.74). RA samples with PTPN2:rs478582 and/or PTPN22:rs2476601 were more positive for MAP than samples without polymorphisms. Combined occurrence of PTPN2:rs478582 and PTPN22:rs2476601 in association with the presence of MAP has significantly increased T-cell response and elevated IFN-γ expression in RA samples. The data suggest that genetic polymorphisms may play vital role in T-cell regulation, susceptibility to mycobacteria and ultimately response to treatment. This is the first study to report the detection of MAP DNA in the blood of RA patients; further studies are needed using larger number of samples.
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Affiliation(s)
- Robert C. Sharp
- Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, United States
| | - Shazia A. Beg
- Health Center, Universtiy of Central Florida College of Medicine, Orlando, FL, United States
| | - Saleh A. Naser
- Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, United States
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24
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Yang G, Bibi S, Du M, Suzuki T, Zhu MJ. Regulation of the intestinal tight junction by natural polyphenols: A mechanistic perspective. Crit Rev Food Sci Nutr 2018; 57:3830-3839. [PMID: 27008212 DOI: 10.1080/10408398.2016.1152230] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Impairment of the epithelial barrier function is closely linked to the pathogenesis of various gastrointestinal diseases, food allergies, type I diabetes, and other systematic diseases. Plant-derived polyphenols are natural secondary metabolites and exert various physiological benefits, including anti-inflammatory, anti-oxidative, anti-carcinogenic, and anti-aging effects. Recent studies also show the role of plant polyphenols in regulation of the intestinal barrier and prevention of intestinal inflammatory diseases. Here we summarize the regulatory pathways and mediators linking polyphenols to their beneficial effects on tight junction and gut epithelial barrier functions, and provide useful information about using polyphenols as nutraceuticals for intestinal diseases.
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Affiliation(s)
- Guan Yang
- a School of Food Science , Washington State University , Pullman , Washington , USA
| | - Shima Bibi
- a School of Food Science , Washington State University , Pullman , Washington , USA
| | - Min Du
- b Department of Animal Science , Washington State University , Pullman , Washington , USA
| | - Takuya Suzuki
- c Department of Biofunctional Science and Technology , Hiroshima University , Higashi-Hiroshima , Japan
| | - Mei-Jun Zhu
- a School of Food Science , Washington State University , Pullman , Washington , USA
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25
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Spalinger MR, Lang S, Gottier C, Dai X, Rawlings DJ, Chan AC, Rogler G, Scharl M. PTPN22 regulates NLRP3-mediated IL1B secretion in an autophagy-dependent manner. Autophagy 2017; 13:1590-1601. [PMID: 28786745 PMCID: PMC5612532 DOI: 10.1080/15548627.2017.1341453] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
A variant within the gene locus encoding PTPN22 (protein tyrosine phosphatase, non-receptor type 22) emerged as an important risk factor for auto-inflammatory disorders, including rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes, but at the same time protects from Crohn disease, one of the 2 main forms of inflammatory bowel diseases. We have previously shown that loss of PTPN22 results in decreased NLRP3 (NLR family pyrin domain containing 3) activation and that this effect is mediated via enhanced NLRP3 phosphorylation. However, it is unclear how phosphorylation of NLRP3 mediates its inhibition. Here, we demonstrate that loss of macroautophagy/autophagy abrogates the inhibitory effect on NLRP3 activation observed upon loss of PTPN22. Phosphorylated, but not nonphosphorylated NLRP3 is found in autophagosomes, indicating that NLRP3 phosphorylation mediates its inactivation via promoting sequestration into phagophores, the precursors to autophagosomes. This finding shows that autophagy and NLRP3 inflammasome activation are connected, and that PTPN22 plays a key role in the regulation of those 2 pathways. Given its role in inflammatory disorders, PTPN22 might be an attractive therapeutic target, and understanding the cellular mechanisms modulated by PTPN22 is of crucial importance.
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Affiliation(s)
- Marianne R Spalinger
- a Division of Gastroenterology and Hepatology , University Hospital Zurich, University of Zurich , Zurich , Switzerland
| | - Silvia Lang
- a Division of Gastroenterology and Hepatology , University Hospital Zurich, University of Zurich , Zurich , Switzerland
| | - Claudia Gottier
- a Division of Gastroenterology and Hepatology , University Hospital Zurich, University of Zurich , Zurich , Switzerland
| | - Xuezhi Dai
- b Department of Pediatrics , University of Washington School of Medicine, and Seattle Children's Research Institute , Seattle , WA , USA
| | - David J Rawlings
- b Department of Pediatrics , University of Washington School of Medicine, and Seattle Children's Research Institute , Seattle , WA , USA
| | - Andrew C Chan
- c Department of Immunology, Department of Translational Immunology, and Department of Pathology , Genentech, Inc. , South San Francisco , CA , USA
| | - Gerhard Rogler
- a Division of Gastroenterology and Hepatology , University Hospital Zurich, University of Zurich , Zurich , Switzerland.,d Zurich Center for Integrative Human Physiology , University of Zurich , Zurich , Switzerland
| | - Michael Scharl
- a Division of Gastroenterology and Hepatology , University Hospital Zurich, University of Zurich , Zurich , Switzerland.,d Zurich Center for Integrative Human Physiology , University of Zurich , Zurich , Switzerland
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26
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Hamerman JA, Pottle J, Ni M, He Y, Zhang ZY, Buckner JH. Negative regulation of TLR signaling in myeloid cells--implications for autoimmune diseases. Immunol Rev 2016; 269:212-27. [PMID: 26683155 DOI: 10.1111/imr.12381] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Toll-like receptors (TLR) are transmembrane pattern recognition receptors that recognize microbial ligands and signal for production of inflammatory cytokines and type I interferon in macrophages and dendritic cells (DC). Whereas TLR-induced inflammatory mediators are required for pathogen clearance, many are toxic to the host and can cause pathological inflammation when over-produced. This is demonstrated by the role of TLR-induced cytokines in autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. Because of the potent effects of TLR-induced cytokines, we have diverse mechanisms to dampen TLR signaling. Here, we highlight three pathways that participate in inhibition of TLR responses in macrophages and DC, and their implications in autoimmunity; A20, encoded by the TNFAIP3 gene, Lyp encoded by the PTPN22 gene, and the BCAP/PI3K pathway. We present new findings that Lyp promotes TLR responses in primary human monocytes and that the autoimmunity risk Lyp620W variant is more effective at promoting TLR-induced interleukin-6 than the non-risk Lyp620R protein. This suggests that Lyp serves to downregulate a TLR inhibitory pathway in monocytes, and we propose that Lyp inhibits the TREM2/DAP12 inhibitory pathway. Overall, these pathways demonstrate distinct mechanisms of negative regulation of TLR responses, and all impact autoimmune disease pathogenesis and treatment.
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Affiliation(s)
- Jessica A Hamerman
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.,Department of Immunology, University of Washington, Seattle, WA, USA
| | - Jessica Pottle
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Minjian Ni
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Yantao He
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Zhong-Yin Zhang
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jane H Buckner
- Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
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27
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Combined Medical and Surgical Approach Improves Healing of Septic Perianal Crohn's Disease. J Am Coll Surg 2016; 223:506-514.e1. [DOI: 10.1016/j.jamcollsurg.2016.05.017] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 05/18/2016] [Accepted: 05/23/2016] [Indexed: 12/16/2022]
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28
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Spalinger MR, Zeitz J, Biedermann L, Rossel JB, Sulz MC, Frei P, Scharl S, Vavricka SR, Fried M, Rogler G, Scharl M. Genotype-Phenotype Associations of the CD-Associated Single Nucleotide Polymorphism within the Gene Locus Encoding Protein Tyrosine Phosphatase Non-Receptor Type 22 in Patients of the Swiss IBD Cohort. PLoS One 2016; 11:e0160215. [PMID: 27467733 PMCID: PMC4964985 DOI: 10.1371/journal.pone.0160215] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 07/16/2016] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Protein tyrosine phosphatase non-receptor type 22 (PTPN22) plays an important role in immune cell function and intestinal homeostasis. The single nucleotide polymorphism (SNP) rs2476601 within the PTPN22 gene locus results in aberrant function of PTPN22 protein and protects from Crohn's disease (CD). Here, we investigated associations of PTPN22 SNP rs2476601 in inflammatory bowel disease (IBD) patients in the Swiss IBD Cohort Study (SIBDCS). METHODS 2'028 SIBDCS patients (1173 CD and 855 ulcerative colitis (UC) patients) were included. The clinical characteristics were analysed for an association with the presence of the PTPN22 SNP rs2476601 genotypes 'homozygous variant' (AA), 'heterozygous' (GA) and 'homozygous wild-type' (GG). RESULTS 13 patients (0.6%) were homozygous variant (AA) for the PTPN22 polymorphism, 269 (13.3%) heterozygous variant (GA) and 1'746 (86.1%) homozygous wild-type (GG). In CD, AA and GA genotypes were associated with less use of steroids and antibiotics, and reduced prevalence of vitamin D and calcium deficiency. In UC the AA and GA genotype was associated with increased use of azathioprine and anti-TNF antibodies, but significantly less patients with the PTPN22 variant featured malabsorption syndrome (p = 0.026). CONCLUSION Our study for the first time addressed how presence of SNP rs2476601 within the PTPN22 gene affects clinical characteristics in IBD-patients. Several factors that correlate with more severe disease were found to be less common in CD patients carrying the A-allele, pointing towards a protective role for this variant in affected CD patients. In UC patients however, we found the opposite trend, suggesting a disease-promoting effect of the A-allele.
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Affiliation(s)
- Marianne R. Spalinger
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Jonas Zeitz
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Luc Biedermann
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Jean-Benoit Rossel
- Institute of Social and Preventive Medicine, Université de Lausanne, Lausanne, Switzerland
| | - Michael C. Sulz
- Division of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Pascal Frei
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Sylvie Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Stephan R. Vavricka
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Michael Fried
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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29
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Roth S, Spalinger MR, Gottier C, Biedermann L, Zeitz J, Lang S, Weber A, Rogler G, Scharl M. Bilberry-Derived Anthocyanins Modulate Cytokine Expression in the Intestine of Patients with Ulcerative Colitis. PLoS One 2016; 11:e0154817. [PMID: 27152519 PMCID: PMC4859486 DOI: 10.1371/journal.pone.0154817] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 04/19/2016] [Indexed: 01/30/2023] Open
Abstract
Background/Aims We previously demonstrated that anthocyanin-rich bilberry extract (ARBE) inhibits IFN-γ-induced signalling and downstream effects in human monocytic cells and ameliorates disease activity in ulcerative colitis (UC) patients. Here, we studied the molecular mechanisms of ARBE-mediated effects in vitro and by analysing colonic tissue and serum samples of UC patients treated with an oral anthocyanin-rich bilberry preparation during an open label clinical trial. Methods Colon specimens obtained during an open pilot study using ARBE for the treatment of mild-to-moderate UC were analyzed by immunohistochemistry. Cytokine levels in patients’ serum were quantified by ELISA. Cell culture experiments were performed using THP-1 monocytic cells. Results ARBE treatment inhibited the expression of IFN-γ-receptor 2 in human THP-1 monocytic cells. Colon biopsies of UC patients who responded to the 6-week long ARBE treatment revealed reduced amounts of the pro-inflammatory cytokines IFN-γ and TNF-α. Levels of phosphorylated (activated) p65-NF-κB were reduced in these patients. Further, patients with successful ARBE treatment featured enhanced levels of Th17-cell specific cytokine IL-22 and immunoregulatory cytokine IL-10 as well as reduced serum levels of TNF-α and MCP-1, but enhanced levels of IL-17A, in contrast to patients that did not reach remission after ARBE treatment. Conclusions Our data suggest a molecular mechanism underlying the anti-inflammatory effects of ARBE treatment in UC patients by modulating T-cell cytokine signalling and inhibiting IFN-γ signal transduction. These data are of particular interest, since ARBE is a promising therapeutic approach for the treatment of IBD.
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Affiliation(s)
- Sofia Roth
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Marianne R. Spalinger
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Claudia Gottier
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Luc Biedermann
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Jonas Zeitz
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Silvia Lang
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Achim Weber
- Institute for Surgical Pathology, University Hospital Zürich, Zurich, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- * E-mail:
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30
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Spalinger MR, Kasper S, Gottier C, Lang S, Atrott K, Vavricka SR, Scharl S, Gutte PM, Grütter MG, Beer HD, Contassot E, Chan AC, Dai X, Rawlings DJ, Mair F, Becher B, Falk W, Fried M, Rogler G, Scharl M. NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22. J Clin Invest 2016; 126:1783-800. [PMID: 27043286 PMCID: PMC4855944 DOI: 10.1172/jci83669] [Citation(s) in RCA: 156] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 02/24/2016] [Indexed: 01/04/2023] Open
Abstract
Inflammasomes form as the result of the intracellular presence of danger-associated molecular patterns and mediate the release of active IL-1β, which influences a variety of inflammatory responses. Excessive inflammasome activation results in severe inflammatory conditions, but physiological IL-1β secretion is necessary for intestinal homeostasis. Here, we have described a mechanism of NLRP3 inflammasome regulation by tyrosine phosphorylation of NLRP3 at Tyr861. We demonstrated that protein tyrosine phosphatase non-receptor 22 (PTPN22), variants in which are associated with chronic inflammatory disorders, dephosphorylates NLRP3 upon inflammasome induction, allowing efficient NLRP3 activation and subsequent IL-1β release. In murine models, PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1β. Conversely, patients with inflammatory bowel disease (IBD) that carried an autoimmunity-associated PTPN22 variant had increased IL-1β levels. Together, our results identify tyrosine phosphorylation as an important regulatory mechanism for NLRP3 that prevents aberrant inflammasome activation.
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Affiliation(s)
- Marianne R. Spalinger
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Stephanie Kasper
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Claudia Gottier
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Silvia Lang
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Kirstin Atrott
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Stephan R. Vavricka
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology and
| | - Sylvie Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Petrus M. Gutte
- Institute of Biochemistry, University of Zurich, Zurich, Switzerland
| | - Markus G. Grütter
- Institute of Biochemistry, University of Zurich, Zurich, Switzerland
| | - Hans-Dietmar Beer
- Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland
| | | | - Andrew C. Chan
- Department of Immunology, Genentech, South San Francisco, California, USA
| | - Xuezhi Dai
- Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA
| | - David J. Rawlings
- Seattle Children’s Research Institute, Division of Immunology, Seattle, Washington, USA
| | - Florian Mair
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Werner Falk
- Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Michael Fried
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology and
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology and
| | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology and
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31
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Kamada N, Rogler G. The Innate Immune System: A Trigger for Many Chronic Inflammatory Intestinal Diseases. Inflamm Intest Dis 2016; 1:70-77. [PMID: 29922660 DOI: 10.1159/000445261] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Accepted: 03/08/2016] [Indexed: 12/31/2022] Open
Abstract
Background Mononuclear phagocytes, such as monocytes, macrophages, and dendritic cells, are important cellular components of the innate immune system that contribute to the pathogenesis of many intestinal inflammatory diseases. Summary While mononuclear phagocytes play a key role in the induction of inflammation in many different tissues through production of pro-inflammatory cytokines and chemokines (such as IL-1, TNF, IL-6, IL-8 and MCP-1), free oxygen radicals (also termed 'oxidative burst'), proteases (such as cathepsins) and tissue-degrading enzymes (such as metalloproteinases), resident macrophages as well as dendritic cells in the intestine display an anergic and 'tolerogenic' phenotype mediating tolerance to commensal bacteria. In recent years many single nucleotide polymorphisms (SNPs) in genes mainly expressed in the above-mentioned cell types have been identified to convey an increased risk of autoimmune diseases. SNPs in the NOD2, ATG16L1 and TNFSF15 genes, which are involved in the function of the innate immune cells, are identified as risk factors for Crohn's disease (CD). Of note, these genes are involved in the different functions in the innate immune cells. For example, while NOD2 is required for intracellular recognition of microbial components, ATG16L1 is involved in autophagy responses against intracellular microbes. Likewise, TNFSF15 contributes to the induction of inflammatory responses by innate immune cells. Furthermore, the frequency of mutations in these genes differs by ethnicity. Genetic variations in the NOD2 and ATG16L1 genes are associated with CD in Caucasians but much less in Eastern Asian populations, whereas SNPs in TNFSF15 are dominated in Asian populations. Thus, different genetic risks may eventually lead to similar impairments in innate immune cells, thereby developing the same disease in Western and Asian patients with CD. Key Messages Despite differences in risk genes, similar mechanisms associated with the innate immune system may trigger autoimmune and chronic inflammatory intestinal diseases in East and West.
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Affiliation(s)
- Nobuhiko Kamada
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Mich., USA
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
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Sharp RC, Abdulrahim M, Naser ES, Naser SA. Genetic Variations of PTPN2 and PTPN22: Role in the Pathogenesis of Type 1 Diabetes and Crohn's Disease. Front Cell Infect Microbiol 2015; 5:95. [PMID: 26734582 PMCID: PMC4689782 DOI: 10.3389/fcimb.2015.00095] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 12/07/2015] [Indexed: 12/12/2022] Open
Abstract
Genome wide association studies have identified several genes that might be associated with increase susceptibility to Type 1 Diabetes (T1D) and Crohn's disease. Both Crohn's disease and T1D have a profound impact on the lives of patients and it is pivotal to investigate the genetic role in patients acquiring these diseases. Understanding the effect of single nucleotide polymorphisms (SNP's) in key genes in patients suffering from T1D and Crohn's disease is crucial to finding an effective treatment and generating novel therapeutic drugs. This review article is focused on the impact of SNP's in PTPN2 (protein tyrosine phosphatase, non-receptor type 2) and PTPN22 (protein tyrosine phosphatase non-receptor type 22) on the development of Crohn's disease and T1D. The PTPN2 gene mutation in T1D patients play a direct role in the destruction of beta cells while in Crohn's disease patients, it modulates the innate immune responses. The PTPN22 gene mutations also play a role in both diseases by modulating intracellular signaling. Examining the mechanism through which these genes increase the susceptibility to both diseases and gaining a better understanding of their structure and function is of vital importance to understand the etiology and pathogenesis of Type 1 Diabetes and Crohn's disease.
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Affiliation(s)
- Robert C Sharp
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida Orlando, FL, USA
| | - Muna Abdulrahim
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida Orlando, FL, USA
| | - Ebraheem S Naser
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida Orlando, FL, USA
| | - Saleh A Naser
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida Orlando, FL, USA
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de Vallière C, Vidal S, Clay I, Jurisic G, Tcymbarevich I, Lang S, Ludwig MG, Okoniewski M, Eloranta JJ, Kullak-Ublick GA, Wagner CA, Rogler G, Seuwen K. The pH-sensing receptor OGR1 improves barrier function of epithelial cells and inhibits migration in an acidic environment. Am J Physiol Gastrointest Liver Physiol 2015. [PMID: 26206859 DOI: 10.1152/ajpgi.00408.2014] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The pH-sensing receptor ovarian cancer G protein-coupled receptor 1 (OGR1; GPR68) is expressed in the gut. Inflammatory bowel disease is typically associated with a decrease in local pH, which may lead to altered epithelial barrier function and subsequent gastrointestinal repair involving epithelial cell adhesion and migration. As the mechanisms underlying the response to pH changes are not well understood, we have investigated OGR1-mediated, pH-dependent signaling pathways in intestinal epithelial cells. Caco-2 cells stably overexpressing OGR1 were created and validated as tools to study OGR1 signaling. Barrier function, migration, and proliferation were measured using electric cell-substrate impedance-sensing technology. Localization of the tight junction proteins zonula occludens protein 1 and occludin and the rearrangement of cytoskeletal actin were examined by confocal microscopy. Paracellular permeability and protein and gene expression analysis using DNA microarrays were performed on filter-grown Caco-2 monolayers. We report that an acidic pH shift from pH 7.8 to 6.6 improved barrier function and stimulated reorganization of filamentous actin with prominent basal stress fiber formation. Cell migration and proliferation during in vitro wound healing were inhibited. Gene expression analysis revealed significant upregulation of genes related to cytoskeleton remodeling, cell adhesion, and growth factor signaling. We conclude that acidic extracellular pH can have a signaling function and impact the physiology of intestinal epithelial cells. The deconstruction of OGR1-dependent signaling may aid our understanding of mucosal inflammation mechanisms.
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Affiliation(s)
- Cheryl de Vallière
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland; Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Solange Vidal
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Ieuan Clay
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Giorgia Jurisic
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Irina Tcymbarevich
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Silvia Lang
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | | | - Michal Okoniewski
- Functional Genomics Center, University of Zurich, Zurich, Switzerland
| | - Jyrki J Eloranta
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
| | - Carsten A Wagner
- Institute of Physiology, University of Zurich, Zurich, Switzerland; and Zurich Center for Integrative Human Physiology, Zurich, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology, Zurich, Switzerland
| | - Klaus Seuwen
- Novartis Institutes for Biomedical Research, Basel, Switzerland;
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Tseng CC, Yen JH, Tsai WC, Ou TT, Wu CC, Sung WY, Hsieh MC, Chang SJ. Reduced incidence of Crohn's disease in systemic sclerosis: a nationwide population study. BMC Musculoskelet Disord 2015; 16:251. [PMID: 26370572 PMCID: PMC4570507 DOI: 10.1186/s12891-015-0693-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 08/21/2015] [Indexed: 12/28/2022] Open
Abstract
Background To date, there has been no studies to evaluate the incidence of Crohn’s disease in systemic sclerosis patients. The goals of this study were to evaluate the incidence of Crohn’s disease and its relationship with sex and age in patients with systemic sclerosis. Methods We enrolled patients with systemic sclerosis and controls from Taiwan’s Registry of Catastrophic Illness Database and National Health Insurance Research Database. Every systemic sclerosis patient was matched to at most three controls by sex, age, month and year of initial diagnosis of systemic sclerosis. The standardized incidence ratio (SIR) of Crohn’s disease in systemic sclerosis patients, and 95 % confidence interval (95 % CI) were calculated. Cox hazard regression was used to calculate the hazard ratio (HR). Results The study enrolled 2,829 patients with systemic sclerosis and 8,257 controls. Male and female patients with systemic sclerosis both had lower rates of incident Crohn’s disease (SIR: 0.18, 95 % CI = 0.05–0.62; SIR: 0.10, 95 % CI = 0.05–0.21, respectively). The risk of incident Crohn’s disease in systemic sclerosis was still lower than in controls when we stratified the patients according to their ages. In Cox hazard regression, the hazard rates of Crohn’s disease were lower in systemic sclerosis patients after adjusting for genders and ages (HR: 0.12, 95 % CI = 0.06–0.21, p < 0.001). Conclusions Systemic sclerosis is associated with decreased incidence of, irrespective of sex and age of the patients.
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Affiliation(s)
- Chia-Chun Tseng
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Jeng-Hsien Yen
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. .,Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan. .,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Wen-Chan Tsai
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Tsan-Teng Ou
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Cheng-Chin Wu
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Wan-Yu Sung
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. .,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Ming-Chia Hsieh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan. .,Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.
| | - Shun-Jen Chang
- Department of Kinesiology, Health and Leisure Studies, National University of Kaohsiung, Kaohsiung, Taiwan.
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Spalinger MR, Scharl M. The role for protein tyrosine phosphatase non-receptor type 22 in regulating intestinal homeostasis. United European Gastroenterol J 2015; 4:325-32. [PMID: 27403297 DOI: 10.1177/2050640615600115] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 07/20/2015] [Indexed: 12/18/2022] Open
Abstract
Inflammatory bowel disease represents a chronic intestinal inflammation. Recent knowledge suggests a crucial role for genetic, immunological and bacterial factors in inflammatory bowel disease pathogenesis. Variations within the gene locus encoding PTPN22 have been associated with inflammatory bowel disease. PTPN22 is critically involved in controlling immune cell activation and thereby plays an important role in maintaining intestinal homeostasis. Although in B and T cells the mechanism showing how PTPN22 affects cell signalling pathways is well studied, its role in myeloid cells remains less defined. Regulation of the innate immune system plays an essential role in the intestine, and levels of PTPN22 in myeloid cells are drastically reduced in the intestine of inflammatory bowel disease patients. Therefore, additional studies to define the role of PTPN22 in myeloid cells might clearly enhance our understanding of how PTPN22 contributes to intestinal homeostasis.
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Affiliation(s)
- Marianne R Spalinger
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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36
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An HNF1α-regulated feedback circuit modulates hepatic fibrogenesis via the crosstalk between hepatocytes and hepatic stellate cells. Cell Res 2015; 25:930-45. [PMID: 26169608 PMCID: PMC4528057 DOI: 10.1038/cr.2015.84] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2014] [Revised: 01/27/2015] [Accepted: 06/02/2015] [Indexed: 12/29/2022] Open
Abstract
Hepatocytes are critical for the maintenance of liver homeostasis, but its involvement in hepatic fibrogenesis remains elusive. Hepatocyte nuclear factor 1α (HNF1α) is a liver-enriched transcription factor that plays a key role in hepatocyte function. Our previous study revealed a significant inhibitory effect of HNF1α on hepatocellular carcinoma. In this study, we report that the expression of HNF1α is significantly repressed in both human and rat fibrotic liver. Knockdown of HNF1α in the liver significantly aggravates hepatic fibrogenesis in either dimethylnitrosamine (DMN) or bile duct ligation (BDL) model in rats. In contrast, forced expression of HNF1α markedly alleviates hepatic fibrosis. HNF1α regulates the transcriptional expression of SH2 domain-containing phosphatase-1 (SHP-1) via directly binding to SHP-1 promoter in hepatocytes. Inhibition of SHP-1 expression abrogates the anti-fibrotic effect of HNF1α in DMN-treated rats. Moreover, HNF1α repression in primary hepatocytes leads to the activation of NF-κB and JAK/STAT pathways and initiates an inflammatory feedback circuit consisting of HNF1α, SHP-1, STAT3, p65, miR-21 and miR-146a, which sustains the deregulation of HNF1α in hepatocytes. More interestingly, a coordinated crosstalk between hepatocytes and hepatic stellate cells (HSCs) participates in this positive feedback circuit and facilitates the progression of hepatocellular damage. Our findings demonstrate that impaired hepatocytes play an active role in hepatic fibrogenesis. Early intervention of HNF1α-regulated inflammatory feedback loop in hepatocytes may have beneficial effects in the treatment of chronic liver diseases.
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Holmes DA, Suto E, Lee WP, Ou Q, Gong Q, Smith HRC, Caplazi P, Chan AC. Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling. ACTA ACUST UNITED AC 2015; 212:1081-93. [PMID: 26077719 PMCID: PMC4493413 DOI: 10.1084/jem.20142130] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 05/15/2015] [Indexed: 02/03/2023]
Abstract
The protein tyrosine phosphatase PTPN22(C1858T) allelic polymorphism is associated with increased susceptibility for development of systemic lupus erythematosus (SLE) and other autoimmune diseases. PTPN22 (also known as LYP) and its mouse orthologue PEP play important roles in antigen and Toll-like receptor signaling in immune cell functions. We demonstrate here that PEP also plays an important inhibitory role in interferon-α receptor (IFNAR) signaling in mice. PEP co-immunoprecipitates with components of the IFNAR signaling complex. Pep(-/-) hematopoietic progenitors demonstrate increased IFNAR signaling, increased IFN-inducible gene expression, and enhanced proliferation and activation compared to Pep(+/+) progenitors in response to IFN-α. In addition, Pep(-/-) mice treated with IFN-α display a profound defect in hematopoiesis, resulting in anemia, thrombocytopenia, and neutropenia when compared to IFN-α-treated Pep(+/+) mice. As SLE patients carrying the PTPN22(C1858T) risk variant have higher serum IFN-α activity, these data provide a molecular basis for how type I IFNs and PTPN22 may cooperate to contribute to lupus-associated cytopenias.
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Affiliation(s)
- Derek A Holmes
- Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080
| | - Eric Suto
- Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080
| | - Wyne P Lee
- Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080
| | - Qinglin Ou
- Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080
| | - Qian Gong
- Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080
| | - Hamish R C Smith
- Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080
| | - Patrick Caplazi
- Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080
| | - Andrew C Chan
- Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080
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Rawlings DJ, Dai X, Buckner JH. The role of PTPN22 risk variant in the development of autoimmunity: finding common ground between mouse and human. THE JOURNAL OF IMMUNOLOGY 2015; 194:2977-84. [PMID: 25795788 DOI: 10.4049/jimmunol.1403034] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The PTPN22 1858T variant was among the first single nucleotide polymorphisms to be associated with multiple autoimmune diseases. Lymphocyte tyrosine phosphatase, a coding variant within the tyrosine phosphatases, is known to participate in AgR signaling; the impact of this variant on the immune response and its role in the development of autoimmunity have been a focus of study. These studies used a series of approaches, including transfected cell lines, animal models, and primary human lymphocytes, and identified multiple alterations in cell signaling and function linked to the PTPN22 variant. Conflicting findings led to questions of how best to study the role of this variant in human autoimmunity. In this review, we discuss these differences and the factors that may account for them, as well as show how an integrated approach can lead to a more complete understanding of the mechanisms that promote autoimmunity in the context of the PTPN22 1858T risk variant.
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Affiliation(s)
- David J Rawlings
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195; Seattle Children's Research Institute, Seattle, WA 98101; and
| | - Xuezhi Dai
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195; Seattle Children's Research Institute, Seattle, WA 98101; and
| | - Jane H Buckner
- Translational Research Program, Benaroya Research Institute, Seattle, WA 98101
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Holgersen K, Kutlu B, Fox B, Serikawa K, Lord J, Hansen AK, Holm TL. High-resolution gene expression profiling using RNA sequencing in patients with inflammatory bowel disease and in mouse models of colitis. J Crohns Colitis 2015; 9:492-506. [PMID: 25795566 DOI: 10.1093/ecco-jcc/jjv050] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Proper interpretation of data from preclinical animal studies requires thorough knowledge of the pathophysiology of both the human disease and animal models. In this study, the expression of inflammatory bowel disease [IBD]-associated genes was characterised in mouse models of colitis to examine the underlying molecular pathways and assess the similarity between the experimental models and human disease. METHODS RNA sequencing was performed on colon biopsies from Crohn's disease [CD] patients, ulcerative colitis [UC] patients and non-IBD controls. Genes shown to be significantly dysregulated in human IBD were used to study gene expression in colons from a piroxicam-accelerated colitis interleukin-10 knockout [PAC IL-10 k.o.], an adoptive transfer [AdTr] and a dextran sulfate sodium [DSS] colitis mouse model. RESULTS Of 115 literature-defined genes linked to IBD, 92 were significantly differentially expressed in inflamed mucosa of CD and/or UC patients compared with non-IBD controls. The most upregulated genes were shared by both diseases, including REG1A, LCN2, NOS2, CXCL1-2, and S100A9. Of those 92 IBD-associated genes, 71 [77%] were significantly dysregulated in PAC IL-10 k.o. mice, whereas 59 [64%] were significantly dysregulated in AdTr mice compared with wild-type controls. Some of the most upregulated genes, including S100a8-9, Nos2, and Lcn2, were shared by the colitis models and correlated with disease activity. CONCLUSIONS IBD and experimental murine colitis have a high degree of similarity in the colonic transcriptional profile, probably secondary to non-specific inflammatory processes. However, differences do exist between models, emphasising the need for careful selection and interpretation of qualified animal models in preclinical research.
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Affiliation(s)
- Kristine Holgersen
- Novo Nordisk-LIFE In Vivo Pharmacology Centre, Frederiksberg, Denmark Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark Department of Immunopharmacology, Novo Nordisk A/S, Maaloev, Denmark
| | - Burak Kutlu
- NNRC-Molecular Immunology, Novo Nordisk Inc., Seattle, WA, USA
| | - Brian Fox
- NNRC-Molecular Immunology, Novo Nordisk Inc., Seattle, WA, USA
| | - Kyle Serikawa
- NNRC-Molecular Immunology, Novo Nordisk Inc., Seattle, WA, USA
| | - James Lord
- Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA, USA
| | - Axel Kornerup Hansen
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
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40
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Guo CC, Deng Y, Ye H, Zhu YZ, Zheng XB. Role of MAPK signaling pathways in inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2015; 23:229-235. [DOI: 10.11569/wcjd.v23.i2.229] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Mitogen-activated protein kinases (MAPKs) are a group of highly conserved serine protein kinases which are distributed in the cytoplasm. MAPK signal transduction pathways play a major role in inflammatory reactions and have a close relation with inflammatory bowel disease (IBD). They could be involved in the regulation of inflammatory mediators as well as IBD-associated genes. This paper reviews the role of MAPK signaling pathways in the pathogenesis of IBD, aiming at providing a new method for the treatment of IBD.
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Abstract
PTPN22 encodes a tyrosine phosphatase that is expressed by haematopoietic cells and functions as a key regulator of immune homeostasis by inhibiting T-cell receptor signalling and by selectively promoting type I interferon responses after activation of myeloid-cell pattern-recognition receptors. A single nucleotide polymorphism of PTPN22, 1858C>T (rs2476601), disrupts an interaction motif in the protein, and is the most important non-HLA genetic risk factor for rheumatoid arthritis and the second most important for juvenile idiopathic arthritis. PTPN22 exemplifies a shared autoimmunity gene, affecting the pathogenesis of systemic lupus erythematosus, vasculitis and other autoimmune diseases. In this Review, we explore the role of PTPN22 in autoimmune connective tissue disease, with particular emphasis on candidate-gene and genome-wide association studies and clinical variability of disease. We also propose a number of PTPN22-dependent functional models of the pathogenesis of autoimmune diseases.
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Abstract
Crohn's disease (CD) is characterized by a breakdown of the intestinal epithelial barrier function leading to an uncontrolled immune response to bacterial antigens. Available data demonstrate that appropriate response and early host defense against invading bacteria are crucial to maintain tolerance towards commensal bacteria. When the mechanisms of early removal of invading bacteria are disturbed, a loss of tolerance and a full-blown adaptive immune reaction, which is mounted against the usually harmless commensal flora, are induced. Dysfunction of autophagy caused by genetic variations within CD susceptibility genes, such as ATG16L1 and IRGM, results in defective handling of intracellular and invading bacteria and causes prolonged survival and defective clearance of those microbes. Dysfunction of ATG16L1 and IRGM has also been shown to cause aberrant Paneth cell function and uncontrolled secretion of proinflammatory cytokines finally resulting in increased susceptibility to bacterial infection and the onset of colitis. Interestingly, autophagy can also be regulated by other CD susceptibility genes, such as NOD2 (nucleotide oligomerization domain 2) or PTPN2 (protein tyrosine phosphatase nonreceptor type 2) and the presence of the CD-associated variations within these genes results in similar effects. Taken together, more and more evidence suggests a close functional correlation between loss of tolerance and defective autophagy in CD patients. Therefore, most likely, the onset of CD is triggered by both a loss of tolerance as well as a dysfunction of autophagy, which finally results in the onset of chronic intestinal inflammation.
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Affiliation(s)
- Marianne R Spalinger
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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Bottini N, Peterson EJ. Tyrosine phosphatase PTPN22: multifunctional regulator of immune signaling, development, and disease. Annu Rev Immunol 2013; 32:83-119. [PMID: 24364806 DOI: 10.1146/annurev-immunol-032713-120249] [Citation(s) in RCA: 155] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inheritance of a coding variant of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is associated with increased susceptibility to autoimmunity and infection. Efforts to elucidate the mechanisms by which the PTPN22-C1858T variant modulates disease risk revealed that PTPN22 performs a signaling function in multiple biochemical pathways and cell types. Capable of both enzymatic activity and adaptor functions, PTPN22 modulates signaling through antigen and innate immune receptors. PTPN22 plays roles in lymphocyte development and activation, establishment of tolerance, and innate immune cell-mediated host defense and immunoregulation. The disease-associated PTPN22-R620W variant protein is likely involved in multiple stages of the pathogenesis of autoimmunity. Establishment of a tolerant B cell repertoire is disrupted by PTPN22-R620W action during immature B cell selection, and PTPN22-R620W alters mature T cell responsiveness. However, after autoimmune attack has initiated tissue injury, PTPN22-R620W may foster inflammation through modulating the balance of myeloid cell-produced cytokines.
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Affiliation(s)
- Nunzio Bottini
- Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037;
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Fousteri G, Liossis SNC, Battaglia M. Roles of the protein tyrosine phosphatase PTPN22 in immunity and autoimmunity. Clin Immunol 2013; 149:556-65. [PMID: 24269925 DOI: 10.1016/j.clim.2013.10.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Revised: 10/09/2013] [Accepted: 10/10/2013] [Indexed: 02/07/2023]
Abstract
PTPN22 is a protein tyrosine phosphatase expressed by the majority of cells belonging to the innate and adaptive immune systems. Polymorphisms in PTPN22 are associated with several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and type 1 diabetes. This review discusses the role of PTPN22 in T and B cells, and its function in innate immune cells, such as monocytes, dendritic cells and NK cells. We focus particularly on the complexity that underlies the function of PTPN22 in the biological processes of the immune system; such complexity has led various research groups to produce rather conflicting data.
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Affiliation(s)
- Georgia Fousteri
- San Raffaele Scientific Institute, Diabetes Research Institute, Via Olgettina 58, Milan, Italy.
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Spalinger MR, Lang S, Vavricka SR, Fried M, Rogler G, Scharl M. Protein tyrosine phosphatase non-receptor type 22 modulates NOD2-induced cytokine release and autophagy. PLoS One 2013; 8:e72384. [PMID: 23991106 PMCID: PMC3753240 DOI: 10.1371/journal.pone.0072384] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 07/09/2013] [Indexed: 11/24/2022] Open
Abstract
Background Variations within the gene locus encoding protein tyrosine phosphatase non-receptor type 22 (PTPN22) are associated with the risk to develop inflammatory bowel disease (IBD). PTPN22 is involved in the regulation of T- and B-cell receptor signaling, but although it is highly expressed in innate immune cells, its function in other signaling pathways is less clear. Here, we study whether loss of PTPN22 controls muramyl-dipeptide (MDP)-induced signaling and effects in immune cells. Material & Methods Stable knockdown of PTPN22 was induced in THP-1 cells by shRNA transduction prior to stimulation with the NOD2 ligand MDP. Cells were analyzed for signaling protein activation and mRNA expression by Western blot and quantitative PCR; cytokine secretion was assessed by ELISA, autophagosome induction by Western blot and immunofluorescence staining. Bone marrow derived dendritic cells (BMDC) were obtained from PTPN22 knockout mice or wild-type animals. Results MDP-treatment induced PTPN22 expression and activity in human and mouse cells. Knockdown of PTPN22 enhanced MDP-induced activation of mitogen-activated protein kinase (MAPK)-isoforms p38 and c-Jun N-terminal kinase as well as canonical NF-κB signaling molecules in THP-1 cells and BMDC derived from PTPN22 knockout mice. Loss of PTPN22 enhanced mRNA levels and secretion of interleukin (IL)-6, IL-8 and TNF in THP-1 cells and PTPN22 knockout BMDC. Additionally, loss of PTPN22 resulted in increased, MDP-mediated autophagy in human and mouse cells. Conclusions Our data demonstrate that PTPN22 controls NOD2 signaling, and loss of PTPN22 renders monocytes more reactive towards bacterial products, what might explain the association of PTPN22 variants with IBD pathogenesis.
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Affiliation(s)
- Marianne R. Spalinger
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Silvia Lang
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Stephan R. Vavricka
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- Division of Gastroenterology and Hepatology, Stadtspital Triemli, Zurich, Switzerland
| | - Michael Fried
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- * E-mail:
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Chang HH, Miaw SC, Tseng W, Sun YW, Liu CC, Tsao HW, Ho IC. PTPN22 modulates macrophage polarization and susceptibility to dextran sulfate sodium-induced colitis. THE JOURNAL OF IMMUNOLOGY 2013; 191:2134-43. [PMID: 23913970 DOI: 10.4049/jimmunol.1203363] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
PTPN22, a protein tyrosine phosphatase expressed mainly in hematopoietic cells, has been linked to many autoimmune diseases. A C-to-T single nucleotide polymorphism (SNP) at position 1858 of human PTPN22 cDNA decreases the risk of Crohn's disease. However, the function of PTPN22 and the mechanism by which this SNP reduces the risk of Crohn's disease are poorly understood. We find that PTPN22 is expressed in macrophages. It suppresses M1 macrophage polarization and reciprocally promotes the expression of M2-associated genes. PTPN22-deficient mice develop severe colitis induced by dextran sulfate sodium, and their intestinal macrophages express higher levels of M1 genes but lower levels of M2-associated genes. Furthermore, the protective T allele of the C1858T SNP is associated with attenuated expression of inflammatory cytokines and a higher level of PTPN22 in human M1 macrophages. This T allele-associated aberrant expression of PTPN22 is partly attributed to an autoinhibition mechanism, in which PTPN22 suppresses its own expression in M1 but not M2 macrophages. Our data not only demonstrate a critical role of PTPN22 in regulating macrophage polarization but also provide a molecular explanation for the protective effect of the C1858T SNP in Crohn's disease.
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Affiliation(s)
- Hui-Hsin Chang
- Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
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