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Husain N, Kumar A, Anbazhagan AN, Gill RK, Dudeja PK. Intestinal luminal anion transporters and their interplay with gut microbiome and inflammation. Am J Physiol Cell Physiol 2025; 328:C1455-C1472. [PMID: 40047092 PMCID: PMC12023768 DOI: 10.1152/ajpcell.00026.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 01/29/2025] [Accepted: 02/28/2025] [Indexed: 04/16/2025]
Abstract
The intestine, as a critical interface between the external environment and the internal body, plays a central role in nutrient absorption, immune regulation, and maintaining homeostasis. The intestinal epithelium, composed of specialized epithelial cells, harbors apical anion transporters that primarily mediate the transport of chloride and bicarbonate ions, essential for maintaining electrolyte balance, pH homeostasis, and fluid absorption/secretion. In addition, the intestine hosts a diverse population of gut microbiota that plays a pivotal role in various physiological processes including nutrient metabolism, immune regulation, and maintenance of intestinal barrier integrity, all of which are critical for host gut homeostasis and health. The anion transporters and gut microbiome are intricately interconnected, where alterations in one can trigger changes in the other, leading to compromised barrier integrity and increasing susceptibility to pathophysiological states including gut inflammation. This review focuses on the interplay of key apical anion transporters including Down-Regulated in Adenoma (DRA, SLC26A3), Putative Anion Transporter-1 (PAT1, SLC26A6), and Cystic Fibrosis Transmembrane Conductance Regulator [CFTR, ATP-binding cassette subfamily C member 7 (ABCC7)] with the gut microbiome, barrier integrity, and their relationship to gut inflammation.
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Affiliation(s)
- Nazim Husain
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, IL, USA
| | - Anoop Kumar
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, IL, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Arivarasu N. Anbazhagan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, IL, USA
| | - Ravinder K Gill
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, IL, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Pradeep. K. Dudeja
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, IL, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
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2
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Sarkar S, Han JX, Azzopardi K, Dhar P, Saeed MA, Day S, Ranganathan S, Sutton P. Protease-activated receptor 1 in the pathogenesis of cystic fibrosis. BMJ Open Respir Res 2025; 12:e002960. [PMID: 39832889 PMCID: PMC12004468 DOI: 10.1136/bmjresp-2024-002960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 11/26/2024] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND The most common cause of death in those with cystic fibrosis (CF) is respiratory failure due to bronchiectasis resulting from repeated cycles of respiratory infection and inflammation. Protease-activated receptor 1 (PAR1) is a cell surface receptor activated by serine proteases including neutrophil elastase, which is recognised as a potent modulator of inflammation. While PAR1 is known to play an important role in regulating inflammation, nothing is known about any potential role of this receptor in CF pathogenesis. METHODS PAR1 (PAR1-/- ) and intestinal-corrected CFTR (Cftr-/- ) deficient mice were crossed to generate double knock-out (DKO) mutants lacking both PAR1 and CFTR, as well as matching sibling single mutant and wildtype (WT) littermate controls. Mice were weighed weekly to 15 weeks of age; then, the lungs and intestines were examined. RESULTS Cftr-deficient mice gained body weight at a significantly slower rate than WT controls and presented with no lung inflammation, but had increased weights of their ilea and proximal colons. DKO mice (lacking both CFTR and PAR1) gained body weight at a similar rate to Cftr-/- mice but only gained weight in their proximal colons. Weight gain in the ilea of Cftr-/- but not DKO mice was associated with increased ileal levels in the pro-inflammatory cytokine interleukin (IL)-6. CONCLUSIONS This study provides the first evidence of PAR1 contributing to the pathological effects of Cftr deficiency in the intestine and suggests a possible effect of PAR1 on the regulation of IL-6 in CF pathogenesis.
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Affiliation(s)
- Sohinee Sarkar
- Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Jia-Xi Han
- Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Kristy Azzopardi
- Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Poshmaal Dhar
- Murdoch Children's Research Institute, Parkville, Victoria, Australia
- School of Medicine, Deakin University, Geelong, Victoria, Australia
| | - Muhammad A Saeed
- Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA
| | - Sophie Day
- Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Sarath Ranganathan
- Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Philip Sutton
- Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
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3
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Najm M, Martignetti L, Cornet M, Kelly-Aubert M, Sermet I, Calzone L, Stoven V. From CFTR to a CF signalling network: a systems biology approach to study Cystic Fibrosis. BMC Genomics 2024; 25:892. [PMID: 39342081 PMCID: PMC11438383 DOI: 10.1186/s12864-024-10752-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 08/30/2024] [Indexed: 10/01/2024] Open
Abstract
BACKGROUND Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the gene coding the Cystic Fibrosis Transmembrane Regulator (CFTR) protein, but its overall physio-pathology cannot be solely explained by the loss of the CFTR chloride channel function. Indeed, CFTR belongs to a yet not fully deciphered network of proteins participating in various signalling pathways. METHODS We propose a systems biology approach to study how the absence of the CFTR protein at the membrane leads to perturbation of these pathways, resulting in a panel of deleterious CF cellular phenotypes. RESULTS Based on publicly available transcriptomic datasets, we built and analyzed a CF network that recapitulates signalling dysregulations. The CF network topology and its resulting phenotypes were found to be consistent with CF pathology. CONCLUSION Analysis of the network topology highlighted a few proteins that may initiate the propagation of dysregulations, those that trigger CF cellular phenotypes, and suggested several candidate therapeutic targets. Although our research is focused on CF, the global approach proposed in the present paper could also be followed to study other rare monogenic diseases.
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Affiliation(s)
- Matthieu Najm
- Center for Computational Biology (CBIO), Mines Paris-PSL, 75006, Paris, France.
- Institut Curie, Université PSL, 75005, Paris, France.
- INSERM U900, 75005, Paris, France.
| | - Loredana Martignetti
- Center for Computational Biology (CBIO), Mines Paris-PSL, 75006, Paris, France
- Institut Curie, Université PSL, 75005, Paris, France
- INSERM U900, 75005, Paris, France
| | - Matthieu Cornet
- Center for Computational Biology (CBIO), Mines Paris-PSL, 75006, Paris, France
- Institut Curie, Université PSL, 75005, Paris, France
- INSERM U900, 75005, Paris, France
- Institut Necker Enfants Malades, INSERM U1151, 75015, Paris, France
| | - Mairead Kelly-Aubert
- Institut Necker Enfants Malades, INSERM U1151, 75015, Paris, France
- Université Paris Cité, 75015, Paris, France
| | - Isabelle Sermet
- Institut Necker Enfants Malades, INSERM U1151, 75015, Paris, France
- Université Paris Cité, 75015, Paris, France
- Centre de Référence Maladies Rares, Mucoviscidose et Maladies Apparentées, Hôpital Necker Enfants Malades AP-HP Centre Paris Cité, 75015, Paris, France
| | - Laurence Calzone
- Center for Computational Biology (CBIO), Mines Paris-PSL, 75006, Paris, France.
- Institut Curie, Université PSL, 75005, Paris, France.
- INSERM U900, 75005, Paris, France.
| | - Véronique Stoven
- Center for Computational Biology (CBIO), Mines Paris-PSL, 75006, Paris, France.
- Institut Curie, Université PSL, 75005, Paris, France.
- INSERM U900, 75005, Paris, France.
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4
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Raza Z, Islam BN, Hachem CY, Cummings LC. Evolving data on risk and current screening recommendations for colorectal cancer in cystic fibrosis: Pre- and posttransplant. Pediatr Pulmonol 2024; 59 Suppl 1:S91-S97. [PMID: 39105336 DOI: 10.1002/ppul.27060] [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: 08/12/2023] [Revised: 04/29/2024] [Accepted: 05/03/2024] [Indexed: 08/07/2024]
Abstract
Advances in treatment for cystic fibrosis (CF), including cystic fibrosis transmembrane conductor regulator (CFTR) modulators, have ushered in an era where patients with CF have much longer life expectancies. This shift in life expectancy demands increased attention to diseases of aging in patients with CF. A notable complication of CF is early-onset colorectal cancer (CRC), which is especially prevalent in patients with severe mutations and after transplant. CFTR acts as a tumor suppressor gene based on knockout models. Lack of CFTR expression promotes carcinogenic processes such as intestinal inflammation and deleterious gut microbiome changes. The consensus Cystic Fibrosis Foundation recommendations advocate treating this population as a high-risk group, using a colonoscopy-only screening strategy starting at age 40 in patients without transplant and at age 30 after transplant. Screening should be considered every 5 years if negative and every 3 years or sooner for patients with adenomatous polyps. Future research will determine the role of noninvasive CRC screening tools in this population, as well as the effects of CFTR modulators on the risk of developing CRC.
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Affiliation(s)
- Zain Raza
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Bianca N Islam
- Department of Medicine, Division of Gastroenterology and Liver Disease, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
- Department of Medicine, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA
| | - Christine Y Hachem
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Linda C Cummings
- Department of Medicine, Division of Gastroenterology and Liver Disease, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
- Department of Medicine, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA
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5
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Suppakitjanusant P, Wang Y, Sivapiromrat AK, Hu C, Binongo J, Hunt WR, Weinstein S, Jathal I, Alvarez JA, Chassaing B, Ziegler TR, Gewirtz AT, Tangpricha V. Impact of high-dose cholecalciferol (vitamin D3) and inulin prebiotic on intestinal and airway microbiota in adults with cystic fibrosis: A 2 × 2 randomized, placebo-controlled, double-blind pilot study. J Clin Transl Endocrinol 2024; 37:100362. [PMID: 39188269 PMCID: PMC11345930 DOI: 10.1016/j.jcte.2024.100362] [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: 04/30/2024] [Revised: 06/26/2024] [Accepted: 07/17/2024] [Indexed: 08/28/2024] Open
Abstract
Background Cystic fibrosis (CF) is a multi-organ disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Individuals with CF often have gastrointestinal (GI) dysbiosis due to chronic inflammation and antibiotic use. Previous studies suggested a role for vitamin D in reversing the GI dysbiosis found in CF. Objective To explore the potential role of a combination of high-dose oral cholecalciferol (vitamin D3) and fermentable dietary fiber, inulin, to impact bacterial composition, richness, and diversity of intestinal and airway microbiota in adults with CF. Methods This was a 2 × 2 factorial, double-blinded, placebo-controlled, randomized, pilot clinical trial in which adults with CF received oral cholecalciferol (vitamin D3) (50,000 IU/week) and/or inulin (12 g/day) for 12 weeks. Thus, there were 4 study groups (n = 10 subjects per group); 1) placebo 2) vitamin D3 3) inulin 4) vitamin D3 plus inulin. Stool and sputum samples were collected at baseline (just before) and after the intervention and were analysed using 16S ribosomal RNA gene sequencing for gut and airway microbiota composition. Statistical analyses assessed alpha and beta diversity to evaluate microbial community changes. Results Of a total of 254 screened participants, 40 eligible participants were randomized to one of the 4 treatment arms. Participants receiving vitamin D3 plus inulin exhibited greater changes in microbiome indexes in both intestinal and airway relative to those in the other study groups. Specific taxonomic changes supported the potential beneficial influence of this combination to mitigate both intestinal and airway dysbiosis in adults with CF. Conclusion This pilot study established that the combination of oral vitamin D3 and the prebiotic inulin was well tolerated over 12 weeks in adults with CF and altered gut and airway bacterial communities. Future research appear warranted to define clinical outcomes and the role of microbiota changes therein with this approach.
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Affiliation(s)
- Pichatorn Suppakitjanusant
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Yanling Wang
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | | | - Chengcheng Hu
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Jose Binongo
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - William R. Hunt
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | | | | | - Jessica A. Alvarez
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Benoit Chassaing
- INSERM U1016, Team “Mucosal Microbiota in Chronic Inflammatory Diseases”, CNRS UMR 8104, Université Paris Cité, Paris, France
| | - Thomas R. Ziegler
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Andrew T. Gewirtz
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Vin Tangpricha
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Atlanta VA Medical Center, Decatur, GA, USA
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Bioelectric regulation of intestinal stem cells. Trends Cell Biol 2022:S0962-8924(22)00234-3. [PMID: 36396487 PMCID: PMC10183058 DOI: 10.1016/j.tcb.2022.10.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/21/2022] [Accepted: 10/24/2022] [Indexed: 11/17/2022]
Abstract
Proper regulation of ion balance across the intestinal epithelium is essential for physiological functions, while ion imbalance causes intestinal disorders with dire health consequences. Ion channels, pumps, and exchangers are vital for regulating ion movements (i.e., bioelectric currents) that control epithelial absorption and secretion. Recent in vivo studies used the Drosophila gut to identify conserved pathways that link regulators of Ca2+, Na+ and Cl- with intestinal stem cell (ISC) proliferation. These studies laid a foundation for using the Drosophila gut to identify conserved proliferative responses triggered by bioelectric regulators. Here, we review these studies, discuss their significance, as well as the advantages of using Drosophila to unravel conserved bioelectrically induced molecular pathways in the intestinal epithelium under physiological, pathophysiological, and regenerative conditions.
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7
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Tan X, Kini A, Römermann D, Seidler U. The NHE3 Inhibitor Tenapanor Prevents Intestinal Obstructions in CFTR-Deleted Mice. Int J Mol Sci 2022; 23:ijms23179993. [PMID: 36077390 PMCID: PMC9456459 DOI: 10.3390/ijms23179993] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 11/30/2022] Open
Abstract
Mutations in the CFTR chloride channel result in intestinal obstructive episodes in cystic fibrosis (CF) patients and in CF animal models. In this study, we explored the possibility of reducing the frequency of obstructive episodes in cftr−/− mice through the oral application of a gut-selective NHE3 inhibitor tenapanor and searched for the underlying mechanisms involved. Sex- and age-matched cftr+/+ and cftr−/− mice were orally gavaged twice daily with 30 mg kg−1 tenapanor or vehicle for a period of 21 days. Body weight and stool water content was assessed daily and gastrointestinal transit time (GTT) once weekly. The mice were sacrificed when an intestinal obstruction was suspected or after 21 days, and stool and tissues were collected for further analysis. Twenty-one day tenapanor application resulted in a significant increase in stool water content and stool alkalinity and a significant decrease in GTT in cftr+/+ and cftr−/− mice. Tenapanor significantly reduced obstructive episodes to 8% compared to 46% in vehicle-treated cftr−/− mice and prevented mucosal inflammation. A decrease in cryptal hyperproliferation, mucus accumulation, and mucosal mast cell number was also observed in tenapanor- compared to vehicle-treated, unobstructed cftr−/− mice. Overall, oral tenapanor application prevented obstructive episodes in CFTR-deficient mice and was safe in cftr+/+ and cftr−/− mice. These results suggest that tenapanor may be a safe and affordable adjunctive therapy in cystic fibrosis patients to alleviate constipation and prevent recurrent DIOS.
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Affiliation(s)
| | | | | | - Ursula Seidler
- Correspondence: ; Tel.: +49-5115-329-427; Fax: +49-5115-328-428
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8
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Huet AS, Dvorshchenko KO, Grebinyk DM, Beregova TV, Ostapchenko LI. Expression of the Cftr, Nfkb1, and Ocln Genes during Restoration of Skin Integrity. CYTOL GENET+ 2022. [DOI: 10.3103/s0095452722030148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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9
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Bhattacharya R, Blankenheim Z, Scott PM, Cormier RT. CFTR and Gastrointestinal Cancers: An Update. J Pers Med 2022; 12:868. [PMID: 35743652 PMCID: PMC9224611 DOI: 10.3390/jpm12060868] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/21/2022] [Accepted: 05/23/2022] [Indexed: 11/17/2022] Open
Abstract
Cystic Fibrosis (CF) is a disease caused by mutations in the CFTR gene that severely affects the lungs as well as extra-pulmonary tissues, including the gastrointestinal (GI) tract. CFTR dysfunction resulting from either mutations or the downregulation of its expression has been shown to promote carcinogenesis. An example is the enhanced risk for several types of cancer in patients with CF, especially cancers of the GI tract. CFTR also acts as a tumor suppressor in diverse sporadic epithelial cancers in many tissues, primarily due to the silencing of CFTR expression via multiple mechanisms, but especially due to epigenetic regulation. This review provides an update on the latest research linking CFTR-deficiency to GI cancers, in both CF patients and in sporadic GI cancers, with a particular focus on cancer of the intestinal tract. It will discuss changes in the tissue landscape linked to CFTR-deficiency that may promote cancer development such as breakdowns in physical barriers, microbial dysbiosis and inflammation. It will also discuss molecular pathways and mechanisms that act upstream to modulate CFTR expression, such as by epigenetic silencing, as well as molecular pathways that act downstream of CFTR-deficiency, such as the dysregulation of the Wnt/β-catenin and NF-κB signaling pathways. Finally, it will discuss the emerging CFTR modulator drugs that have shown promising results in improving CFTR function in CF patients. The potential impact of these modulator drugs on the treatment and prevention of GI cancers can provide a new example of personalized cancer medicine.
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Affiliation(s)
| | | | - Patricia M. Scott
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA or (R.B.); (Z.B.)
| | - Robert T. Cormier
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA or (R.B.); (Z.B.)
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10
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Dong ZW, Liu H, Su FF, Fan XZ, Zhang Y, Liu P. Cystic fibrosis transmembrane conductance regulator prevents ischemia/reperfusion induced intestinal apoptosis via inhibiting PI3K/AKT/NF-κB pathway. World J Gastroenterol 2022; 28:918-932. [PMID: 35317058 PMCID: PMC8908288 DOI: 10.3748/wjg.v28.i9.918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/14/2021] [Accepted: 01/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Intestinal ischemia/reperfusion (I/R) injury is a fatal syndrome that occurs under many clinical scenarios. The apoptosis of intestinal cells caused by ischemia can cause cell damage and provoke systemic dysfunction during reperfusion. However, the mechanism of I/R-induced apoptosis remains unclear. Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride channel. Few researchers have paid attention to its role in intestinal I/R injury, or the relationship between CFTR and intestinal apoptosis induced by hypoxia/reoxygenation (H/R).
AIM To investigate the effects of CFTR on I/R-induced intestinal apoptosis and its underlying molecular mechanisms.
METHODS An intestinal I/R injury model was established in mice with superior mesenteric artery occlusion, and Caco2 cells were subjected to H/R for the simulation of I/R in vivo.
RESULTS The results suggested that CFTR overexpression significantly increased the Caco2 cell viability and decreased cell apoptosis induced by the H/R. Interestingly, we found that the translocation of p65, an NF-κB member, from the cytoplasm to the nucleus after H/R treatment can be reversed by the overexpression of CFTR, the NF-κB P65 would return from the nucleus to the cytoplasm as determined by immunostaining. We also discovered that CFTR inhibited cell apoptosis in the H/R-treated cells, and this effect was significantly curbed by the NF-κB activator BA, AKT inhibitor GSK690693 and the PI3K inhibitor LY294002. Moreover, we demonstrated that CFTR overexpression could reverse the decreased PI3K/AKT expression induced by the I/R treatment in vivo or H/R treatment in vitro.
CONCLUSION The results of the present study indicate that the overexpression of CFTR protects Caco2 cells from H/R-induced apoptosis; furthermore, it also inhibits H/R-induced apoptosis through the PI3K/AKT/NF-κB signaling pathway in H/R-treated Caco2 cells and intestinal tissues.
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Affiliation(s)
- Zhi-Wei Dong
- Department of General Surgery, Air Force Medical Center, Beijing 100000, China
| | - Hui Liu
- Department of Gastroenterology, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Fei-Fei Su
- Department of Cardiology, Air Force Medical Center, Beijing 100000, China
| | - Xiao-Zhou Fan
- Department of Ultrasound, Air Force Medical Center, Beijing 100000, China
| | - Yong Zhang
- School of Chemistry and Biological Engineering, University of Science and Technology, Beijing 100000, China
| | - Peng Liu
- Research Laboratory of Aero-Medical Support, Air Force Medical Center, Beijing 100000, China
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11
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Tam RY, van Dorst JM, McKay I, Coffey M, Ooi CY. Intestinal Inflammation and Alterations in the Gut Microbiota in Cystic Fibrosis: A Review of the Current Evidence, Pathophysiology and Future Directions. J Clin Med 2022; 11:649. [PMID: 35160099 PMCID: PMC8836727 DOI: 10.3390/jcm11030649] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/22/2022] [Accepted: 01/25/2022] [Indexed: 12/12/2022] Open
Abstract
Cystic fibrosis (CF) is a life-limiting autosomal recessive multisystem disease. While its burden of morbidity and mortality is classically associated with pulmonary disease, CF also profoundly affects the gastrointestinal (GI) tract. Chronic low-grade inflammation and alterations to the gut microbiota are hallmarks of the CF intestine. The etiology of these manifestations is likely multifactorial, resulting from cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, a high-fat CF diet, and the use of antibiotics. There may also be a bidirectional pathophysiological link between intestinal inflammation and changes to the gut microbiome. Additionally, a growing body of evidence suggests that these GI manifestations may have significant clinical associations with growth and nutrition, quality of life, and respiratory function in CF. As such, the potential utility of GI therapies and long-term GI outcomes are areas of interest in CF. Further research involving microbial modulation and multi-omics techniques may reveal novel insights. This article provides an overview of the current evidence, pathophysiology, and future research and therapeutic considerations pertaining to intestinal inflammation and alterations in the gut microbiota in CF.
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Affiliation(s)
- Rachel Y. Tam
- Discipline of Paediatrics & Child Health, Randwick Clinical Campus, School of Clinical Medicine, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (R.Y.T.); (J.M.v.D.); (M.C.)
| | - Josie M. van Dorst
- Discipline of Paediatrics & Child Health, Randwick Clinical Campus, School of Clinical Medicine, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (R.Y.T.); (J.M.v.D.); (M.C.)
| | - Isabelle McKay
- Wagga Wagga Base Hospital, Wagga Wagga, NSW 2650, Australia;
| | - Michael Coffey
- Discipline of Paediatrics & Child Health, Randwick Clinical Campus, School of Clinical Medicine, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (R.Y.T.); (J.M.v.D.); (M.C.)
- Department of Gastroenterology, Sydney Children’s Hospital Randwick, Sydney, NSW 2031, Australia
| | - Chee Y. Ooi
- Discipline of Paediatrics & Child Health, Randwick Clinical Campus, School of Clinical Medicine, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia; (R.Y.T.); (J.M.v.D.); (M.C.)
- Department of Gastroenterology, Sydney Children’s Hospital Randwick, Sydney, NSW 2031, Australia
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12
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Whittamore JM, Hatch M. Oxalate Flux Across the Intestine: Contributions from Membrane Transporters. Compr Physiol 2021; 12:2835-2875. [PMID: 34964122 DOI: 10.1002/cphy.c210013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Epithelial oxalate transport is fundamental to the role occupied by the gastrointestinal (GI) tract in oxalate homeostasis. The absorption of dietary oxalate, together with its secretion into the intestine, and degradation by the gut microbiota, can all influence the excretion of this nonfunctional terminal metabolite in the urine. Knowledge of the transport mechanisms is relevant to understanding the pathophysiology of hyperoxaluria, a risk factor in kidney stone formation, for which the intestine also offers a potential means of treatment. The following discussion presents an expansive review of intestinal oxalate transport. We begin with an overview of the fate of oxalate, focusing on the sources, rates, and locations of absorption and secretion along the GI tract. We then consider the mechanisms and pathways of transport across the epithelial barrier, discussing the transcellular, and paracellular components. There is an emphasis on the membrane-bound anion transporters, in particular, those belonging to the large multifunctional Slc26 gene family, many of which are expressed throughout the GI tract, and we summarize what is currently known about their participation in oxalate transport. In the final section, we examine the physiological stimuli proposed to be involved in regulating some of these pathways, encompassing intestinal adaptations in response to chronic kidney disease, metabolic acid-base disorders, obesity, and following gastric bypass surgery. There is also an update on research into the probiotic, Oxalobacter formigenes, and the basis of its unique interaction with the gut epithelium. © 2021 American Physiological Society. Compr Physiol 11:1-41, 2021.
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Affiliation(s)
- Jonathan M Whittamore
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Marguerite Hatch
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
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13
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SLC26A9 is selected for endoplasmic reticulum associated degradation (ERAD) via Hsp70-dependent targeting of the soluble STAS domain. Biochem J 2021; 478:4203-4220. [PMID: 34821356 PMCID: PMC8826537 DOI: 10.1042/bcj20210644] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/23/2021] [Accepted: 11/24/2021] [Indexed: 12/24/2022]
Abstract
SLC26A9, a member of the solute carrier protein family, transports chloride ions across various epithelia. SLC26A9 also associates with other ion channels and transporters linked to human health, and in some cases these heterotypic interactions are essential to support the biogenesis of both proteins. Therefore, understanding how this complex membrane protein is initially folded might provide new therapeutic strategies to overcome deficits in the function of SLC26A9 partners, one of which is associated with Cystic Fibrosis. To this end, we developed a novel yeast expression system for SLC26A9. This facile system has been used extensively with other ion channels and transporters to screen for factors that oversee protein folding checkpoints. As commonly observed for other channels and transporters, we first noted that a substantial fraction of SLC26A9 is targeted for endoplasmic reticulum associated degradation (ERAD), which destroys folding-compromised proteins in the early secretory pathway. We next discovered that ERAD selection requires the Hsp70 chaperone, which can play a vital role in ERAD substrate selection. We then created SLC26A9 mutants and found that the transmembrane-rich domain of SLC26A9 was quite stable, whereas the soluble cytosolic STAS domain was responsible for Hsp70-dependent ERAD. To support data obtained in the yeast model, we were able to recapitulate Hsp70-facilitated ERAD of the STAS domain in human tissue culture cells. These results indicate that a critical barrier to nascent membrane protein folding can reside within a specific soluble domain, one that is monitored by components associated with the ERAD machinery.
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14
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Maniam P, Essilfie AT, Kalimutho M, Ling D, Frazer DM, Phipps S, Anderson GJ, Reid DW. Increased susceptibility of cystic fibrosis airway epithelial cells to ferroptosis. Biol Res 2021; 54:38. [PMID: 34903297 PMCID: PMC8670191 DOI: 10.1186/s40659-021-00361-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/28/2021] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Defective chloride transport in airway epithelial cells (AECs) and the associated lung disease are the main causes of morbidity and early mortality in cystic fibrosis (CF). Abnormal airway iron homeostasis and the presence of lipid peroxidation products, indicative of oxidative stress, are features of CF lung disease. RESULTS Here, we report that CF AECs (IB3-1) are susceptible to ferroptosis, a type of cell death associated with iron accumulation and lipid peroxidation. Compared to isogenic CFTR corrected cells (C38), the IB3-1 cells showed increased susceptibility to cell death upon exposure to iron in the form of ferric ammonium citrate (FAC) and the ferroptosis inducer, erastin. This phenotype was accompanied by accumulation of intracellular ferrous iron and lipid peroxides and the extracellular release of malondialdehyde, all indicative of redox stress, and increased levels of lactate dehydrogenase in the culture supernatant, indicating enhanced cell injury. The ferric iron chelator deferoxamine (DFO) and the lipophilic antioxidant ferrostatin-1 inhibited FAC and erastin induced ferroptosis in IB3-1 cells. Glutathione peroxidase 4 (GPX4) expression was decreased in IB3-1 cells treated with FAC and erastin, but was unchanged in C38 AECs. Necroptosis appeared to be involved in the enhanced susceptibility of IB3-1 AECs to ferroptosis, as evidenced by partial cell death rescue with necroptosis inhibitors and enhanced mixed lineage kinase domain-like (MLKL) localisation to the plasma membrane. CONCLUSION These studies suggest that the increased susceptibility of CF AECs to ferroptosis is linked to abnormal intracellular ferrous iron accumulation and reduced antioxidant defences. In addition, the process of ferroptotic cell death in CF AECs does not appear to be a single entity and for the first time we describe necroptosis as a potential contributory factor. Iron chelation and antioxidant treatments may be promising therapeutic interventions in cystic fibrosis.
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Affiliation(s)
- Pramila Maniam
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Ama-Tawiah Essilfie
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Murugan Kalimutho
- Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Dora Ling
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - David M Frazer
- Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Simon Phipps
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Gregory J Anderson
- Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
- School of Chemistry and Molecular Bioscience, University of Queensland, St Lucia, Australia
| | - David W Reid
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
- Adult Cystic Fibrosis Centre, The Prince Charles Hospital, Chermside, Australia.
- Lung Inflammation and Infection Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Herston, QLD, 4003, Australia.
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15
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Chandrasekaran A, Dittlau KS, Corsi GI, Haukedal H, Doncheva NT, Ramakrishna S, Ambardar S, Salcedo C, Schmidt SI, Zhang Y, Cirera S, Pihl M, Schmid B, Nielsen TT, Nielsen JE, Kolko M, Kobolák J, Dinnyés A, Hyttel P, Palakodeti D, Gorodkin J, Muddashetty RS, Meyer M, Aldana BI, Freude KK. Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3. Stem Cell Reports 2021; 16:2736-2751. [PMID: 34678206 PMCID: PMC8581052 DOI: 10.1016/j.stemcr.2021.09.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 12/24/2022] Open
Abstract
Frontotemporal dementia type 3 (FTD3), caused by a point mutation in the charged multivesicular body protein 2B (CHMP2B), affects mitochondrial ultrastructure and the endolysosomal pathway in neurons. To dissect the astrocyte-specific impact of mutant CHMP2B expression, we generated astrocytes from human induced pluripotent stem cells (hiPSCs) and confirmed our findings in CHMP2B mutant mice. Our data provide mechanistic insights into how defective autophagy causes perturbed mitochondrial dynamics with impaired glycolysis, increased reactive oxygen species, and elongated mitochondrial morphology, indicating increased mitochondrial fusion in FTD3 astrocytes. This shift in astrocyte homeostasis triggers a reactive astrocyte phenotype and increased release of toxic cytokines, which accumulate in nuclear factor kappa b (NF-κB) pathway activation with increased production of CHF, LCN2, and C3 causing neurodegeneration.
FTD3 iPSC-derived astrocytes display impaired autophagy Impaired autophagy affects mitochondria turnover, glucose hypometabolism and TCA cycle FTD3 astrocytes contribute to reactive gliosis by increased C3, LCN2, IL6, and IL8 Reactive astrocyte phenotypes are present in both in vitro and in vivo models
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Affiliation(s)
- Abinaya Chandrasekaran
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg 1870, Denmark
| | - Katarina Stoklund Dittlau
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg 1870, Denmark
| | - Giulia I Corsi
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg 1870, Denmark; Center for Non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg 1871, Denmark
| | - Henriette Haukedal
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg 1870, Denmark
| | - Nadezhda T Doncheva
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg 1870, Denmark; Center for Non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg 1871, Denmark; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Sarayu Ramakrishna
- Institute for Stem Cell Science and Regenerative Medicine, Bangalore 560065, India; The University of Trans-Disciplinary Health Sciences and Technology, Bangalore 560064, India
| | - Sheetal Ambardar
- Institute for Stem Cell Science and Regenerative Medicine, Bangalore 560065, India; National Center for Biological Sciences, Tata Institute of Fundamental Research, Bangalore 560065, India
| | - Claudia Salcedo
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark
| | - Sissel I Schmidt
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark
| | - Yu Zhang
- Department of Experimental Medical Science, Wallenberg Center for Molecular Medicine and Lund Stem Cell Center, Lund University, Lund 22184, Sweden
| | - Susanna Cirera
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg 1870, Denmark
| | - Maria Pihl
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg 1870, Denmark
| | | | - Troels Tolstrup Nielsen
- Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
| | - Jørgen E Nielsen
- Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
| | - Miriam Kolko
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark; Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, Copenhagen 2100, Denmark
| | | | | | - Poul Hyttel
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg 1870, Denmark
| | - Dasaradhi Palakodeti
- Institute for Stem Cell Science and Regenerative Medicine, Bangalore 560065, India
| | - Jan Gorodkin
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg 1870, Denmark; Center for Non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg 1871, Denmark
| | - Ravi S Muddashetty
- Institute for Stem Cell Science and Regenerative Medicine, Bangalore 560065, India
| | - Morten Meyer
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; Department of Neurology, Odense University Hospital, 5000 Odense, Denmark
| | - Blanca I Aldana
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark
| | - Kristine K Freude
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg 1870, Denmark.
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16
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ABCC7/CFTR Expression Is Associated with the Clinical Course of Ulcerative Colitis Patients. Gastroenterol Res Pract 2021; 2021:5536563. [PMID: 34512749 PMCID: PMC8426104 DOI: 10.1155/2021/5536563] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 07/01/2021] [Accepted: 08/17/2021] [Indexed: 12/28/2022] Open
Abstract
Inflammatory bowel disease includes ulcerative colitis (UC) and Crohn's disease (CD) of unknown etiology. The expression of ATP-binding cassette (ABC) family proteins has been associated with drug resistance and development of UC. The cystic fibrosis transmembrane conductance regulator (CFTR) or also known as ABCC7 is involved in the inflammatory chronic response. The aim of this study was to evaluate the role of ABCC7/CFTR in UC patients and normal controls without inflammation. This is an exploratory, observational, and cross-sectional study that included a total of 62 patients with UC and normal controls. Gene expression of CFTR was measured by RT-PCR, and protein expression of CFTR was determined by western blot analysis. We found a significant downregulation of the CFTR gene expression in patients with active UC compared to normal controls without inflammation (P < 0.004); even the gene expression of CFTR was decreased in remission UC patients compared to normal controls without inflammation (P = 0.04). The CFTR gene expression was associated with the clinical course of UC and the protein expression of CFTR was decreased in active UC patients compared to normal controls without inflammation suggesting that this molecule might play a role in the inflammation in UC patients.
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17
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Declercq M, de Zeeuw P, Conchinha NV, Geldhof V, Ramalho AS, García-Caballero M, Brepoels K, Ensinck M, Carlon MS, Bird MJ, Vinckier S, Proesmans M, Vermeulen F, Dupont L, Ghesquière B, Dewerchin M, Carmeliet P, Cassiman D, Treps L, Eelen G, Witters P. Transcriptomic analysis of CFTR-impaired endothelial cells reveals a pro-inflammatory phenotype. Eur Respir J 2021; 57:13993003.00261-2020. [PMID: 33184117 DOI: 10.1183/13993003.00261-2020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 10/04/2020] [Indexed: 12/15/2022]
Abstract
Cystic fibrosis (CF) is a life-threatening disorder characterised by decreased pulmonary mucociliary and pathogen clearance, and an exaggerated inflammatory response leading to progressive lung damage. CF is caused by bi-allelic pathogenic variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel. CFTR is expressed in endothelial cells (ECs) and EC dysfunction has been reported in CF patients, but a role for this ion channel in ECs regarding CF disease progression is poorly described.We used an unbiased RNA sequencing approach in complementary models of CFTR silencing and blockade (by the CFTR inhibitor CFTRinh-172) in human ECs to characterise the changes upon CFTR impairment. Key findings were further validated in vitro and in vivo in CFTR-knockout mice and ex vivo in CF patient-derived ECs.Both models of CFTR impairment revealed that EC proliferation, migration and autophagy were downregulated. Remarkably though, defective CFTR function led to EC activation and a persisting pro-inflammatory state of the endothelium with increased leukocyte adhesion. Further validation in CFTR-knockout mice revealed enhanced leukocyte extravasation in lung and liver parenchyma associated with increased levels of EC activation markers. In addition, CF patient-derived ECs displayed increased EC activation markers and leukocyte adhesion, which was partially rescued by the CFTR modulators VX-770 and VX-809.Our integrated analysis thus suggests that ECs are no innocent bystanders in CF pathology, but rather may contribute to the exaggerated inflammatory phenotype, raising the question of whether normalisation of vascular inflammation might be a novel therapeutic strategy to ameliorate the disease severity of CF.
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Affiliation(s)
- Mathias Declercq
- Dept of Development and Regeneration, CF Centre, Woman and Child, KU Leuven, Leuven, Belgium.,Laboratory of Angiogenesis and Vascular Metabolism, Centre for Cancer Biology, VIB, Leuven, Belgium.,Laboratory of Angiogenesis and Vascular Metabolism, Dept of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Pauline de Zeeuw
- Laboratory of Angiogenesis and Vascular Metabolism, Centre for Cancer Biology, VIB, Leuven, Belgium.,Laboratory of Angiogenesis and Vascular Metabolism, Dept of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Nadine V Conchinha
- Laboratory of Angiogenesis and Vascular Metabolism, Centre for Cancer Biology, VIB, Leuven, Belgium.,Laboratory of Angiogenesis and Vascular Metabolism, Dept of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Vincent Geldhof
- Laboratory of Angiogenesis and Vascular Metabolism, Centre for Cancer Biology, VIB, Leuven, Belgium.,Laboratory of Angiogenesis and Vascular Metabolism, Dept of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Anabela S Ramalho
- Stem Cell and Developmental Biology, CF Centre, Woman and Child, KU Leuven, Leuven, Belgium
| | - Melissa García-Caballero
- Laboratory of Angiogenesis and Vascular Metabolism, Centre for Cancer Biology, VIB, Leuven, Belgium.,Laboratory of Angiogenesis and Vascular Metabolism, Dept of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Katleen Brepoels
- Laboratory of Angiogenesis and Vascular Metabolism, Centre for Cancer Biology, VIB, Leuven, Belgium.,Laboratory of Angiogenesis and Vascular Metabolism, Dept of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Marjolein Ensinck
- Laboratory for Molecular Virology and Drug Discovery, Dept of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Marianne S Carlon
- Laboratory for Molecular Virology and Drug Discovery, Dept of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Matthew J Bird
- Laboratory of Hepatology, Dept of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.,Metabolomics Expertise Centre, Centre for Cancer Biology, VIB, Leuven, Belgium
| | - Stefan Vinckier
- Laboratory of Angiogenesis and Vascular Metabolism, Centre for Cancer Biology, VIB, Leuven, Belgium.,Laboratory of Angiogenesis and Vascular Metabolism, Dept of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | | | - François Vermeulen
- Dept of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Lieven Dupont
- Dept of Pneumology, University Hospitals Leuven, Leuven, Belgium
| | - Bart Ghesquière
- Metabolomics Expertise Centre, Centre for Cancer Biology, VIB, Leuven, Belgium.,Metabolomics Expertise Centre, Dept of Oncology, KU Leuven, Leuven, Belgium
| | - Mieke Dewerchin
- Laboratory of Angiogenesis and Vascular Metabolism, Centre for Cancer Biology, VIB, Leuven, Belgium.,Laboratory of Angiogenesis and Vascular Metabolism, Dept of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Centre for Cancer Biology, VIB, Leuven, Belgium.,Laboratory of Angiogenesis and Vascular Metabolism, Dept of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - David Cassiman
- Laboratory of Hepatology, Dept of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.,Centre of Metabolic Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Lucas Treps
- Laboratory of Angiogenesis and Vascular Metabolism, Centre for Cancer Biology, VIB, Leuven, Belgium.,Laboratory of Angiogenesis and Vascular Metabolism, Dept of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium.,Equal co-authorship
| | - Guy Eelen
- Laboratory of Angiogenesis and Vascular Metabolism, Centre for Cancer Biology, VIB, Leuven, Belgium.,Laboratory of Angiogenesis and Vascular Metabolism, Dept of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium.,Equal co-authorship
| | - Peter Witters
- Dept of Development and Regeneration, CF Centre, Woman and Child, KU Leuven, Leuven, Belgium.,Dept of Paediatrics, University Hospitals Leuven, Leuven, Belgium.,Centre of Metabolic Diseases, University Hospitals Leuven, Leuven, Belgium.,Equal co-authorship
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18
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J Burton S, Hachem C, Abraham JM. Luminal Gastrointestinal Manifestations of Cystic Fibrosis. Curr Gastroenterol Rep 2021; 23:4. [PMID: 33758994 DOI: 10.1007/s11894-021-00806-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2021] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW People with cystic fibrosis (CF) are living longer. General age-related and CF-specific gastrointestinal symptoms are increasingly recognized. In this article, we review the latest data on luminal gastrointestinal manifestations in CF. RECENT FINDINGS People with CF have increased incidence of gastroesophageal reflux disease symptoms and often prescribed proton-pump inhibitors (PPI). PPI use may increase risk of pulmonary exacerbations. Evidence to support gastric fundoplication to improve pulmonary outcomes is limited. Features of intestinal dysmotility are common. There are distinct differences in the gut microbiome in the CF population which may have clinical implications. CF is a possible hereditary digestive cancer syndrome, particularly in regard to colorectal cancer (CRC) with earlier incidence of CRC and advanced colonic neoplasia. Early screening colonoscopy is warranted in the CF population. Gastrointestinal manifestations in CF are prevalent across all digestive organs. More study on the effect of interventions for symptomatic treatment and cancer screening is needed.
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Affiliation(s)
- Samuel J Burton
- Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MI, USA
| | - Christine Hachem
- Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MI, USA
| | - James M Abraham
- Department of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
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19
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Trapp S, Aghdassi AA, Glaubitz J, Sendler M, Weiss FU, Kühn JP, Kromrey ML, Mahajan UM, Pallagi P, Rakonczay Z, Venglovecz V, Lerch MM, Hegyi P, Mayerle J. Pancreatitis severity in mice with impaired CFTR function but pancreatic sufficiency is mediated via ductal and inflammatory cells-Not acinar cells. J Cell Mol Med 2021; 25:4658-4670. [PMID: 33682322 PMCID: PMC8107082 DOI: 10.1111/jcmm.16404] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 02/09/2021] [Accepted: 02/11/2021] [Indexed: 02/06/2023] Open
Abstract
Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) are an established risk factor for cystic fibrosis (CF) and chronic pancreatitis. Whereas patients with CF usually develop complete exocrine pancreatic insufficiency, pancreatitis patients with CFTR mutations have mostly preserved exocrine pancreatic function. We therefore used a strain of transgenic mice with significant residual CFTR function (CFTRtm1HGU ) to induce pancreatitis experimentally by serial caerulein injections. Protease activation and necrosis were investigated in isolated acini, disease severity over 24h, pancreatic function by MRI, isolated duct stimulation and faecal chymotrypsin, and leucocyte function by ex vivo lipopolysaccharide (LPS) stimulation. Pancreatic and lung injury were more severe in CFTRtm1HGU but intrapancreatic trypsin and serum enzyme activities higher than in wild-type controls only at 8h, a time interval previously attributed to leucocyte infiltration. CCK-induced trypsin activation and necrosis in acini from CFTRtm1HGU did not differ from controls. Fluid and bicarbonate secretion were greatly impaired, whereas faecal chymotrypsin remained unchanged. LPS stimulation of splenocytes from CFTRtm1HGU resulted in increased INF-γ and IL-6, but decreased IL-10 secretion. CFTR mutations that preserve residual pancreatic function significantly increase the severity of experimental pancreatitis-mostly via impairing duct cell function and a shift towards a pro-inflammatory phenotype, not by rendering acinar cells more susceptible to pathological stimuli.
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Affiliation(s)
- Simon Trapp
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Ali A Aghdassi
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Juliane Glaubitz
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Matthias Sendler
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Frank Ulrich Weiss
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Jens Peter Kühn
- Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany
| | - Marie-Luise Kromrey
- Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany
| | - Ujjwal M Mahajan
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.,Department of Medicine II, Ludwig-Maximilians University Munich, Munich, Germany
| | - Petra Pallagi
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Zoltán Rakonczay
- Department of Pathophysiology, University of Szeged, Szeged, Hungary
| | - Viktória Venglovecz
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Peter Hegyi
- Department of Translational Medicine/First Department of Medicine, Medical School, Institute for Translational Medicine, Pécs, Hungary
| | - Julia Mayerle
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.,Department of Medicine II, Ludwig-Maximilians University Munich, Munich, Germany
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20
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Liu X, Chen Y, You B, Peng Y, Chen Y, Yang Z, Zhang Y, Chen J. Molecular mechanism mediating enteric bacterial translocation after severe burn: the role of cystic fibrosis transmembrane conductance regulator. BURNS & TRAUMA 2021; 9:tkaa042. [PMID: 33501367 PMCID: PMC7809362 DOI: 10.1093/burnst/tkaa042] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/28/2020] [Indexed: 11/23/2022]
Abstract
Background Gut ischemia and hypoxia post severe burn leads to breakdown of intestinal epithelial
barrier and enteric bacterial translocation (EBT), resulting in serious complications,
such as systemic inflammatory response syndrome, sepsis and multiple organ failure.
Cystic fibrosis transmembrane conductance regulator (CFTR) is known to be downregulated
by hypoxia and modulate junctional complexes, which are crucial structures maintaining
the intestinal barrier. This study aimed to investigate whether CFTR plays a role in
both regulating the intestinal barrier and mediating EBT post severe burn, as well as
the signaling pathways involved in these processes. Methods An in vitro Caco-2 cell model subjected to hypoxic injury and an
in vivo mouse model with a 30% total body surface area full-thickness
dermal burn were established. DF 508 mice (mice with F508del CFTR gene mutation) were
used as an in vivo model to further demonstrate the role of CFTR in maintaining normal
intestinal barrier function. QRT-PCR, western blot, ELISA, TER assay and
immunofluorescence staining were used to detect the expression and localization of CFTR
and tight junction proteins, as well as the function of tight junctions. Results Our data indicated that, in Caco-2 cells, the hypoxia condition significantly reduced
CFTR expression; activated extracellular signal-regulated kinase and nuclear factor-κB
signaling; elevated secretion of inflammatory factors (tumor necrosis factor-α,
interleukin-1β and interleukin-8); downregulated zonula occludens-1, occludin and
E-cadherin expression; decreased transepithelial electrical resistance values; and led
to a cellular mislocation of ZO-1. More importantly, knockdown of CFTR caused similar
alterations. The upregulation of inflammatory factors and downregulation of tight
junction proteins (ZO-1 and occludin) induced by knockdown of CFTR could be reversed by
specific extracellular signal-regulated kinase or nuclear factor-κB inhibition. In
support of the in vitro data, exuberant secretion of pro-inflammatory
mediators and EBT was observed in the intestine of severely burnt mice in
vivo. EBT occurred in DF508 mice (mice with the F508del CFTR gene mutation),
accompanied by augmented tumor necrosis factor-α, interleukin-1β and interleukin-8
levels in the ileum compared to wildtype mice. In addition, vitamin D3 was shown to
protect the intestinal epithelial barrier from hypoxic injury. Conclusions Collectively, the present study illustrated that CFTR and downstream signaling were
critical in modulating the intestinal epithelial junction and EBT post severe burn.
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Affiliation(s)
- Xinzhu Liu
- State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Proteomics Disease, Institute of Burn Research, Southwest Hospital (the First Affiliated Hospital), Third Military Medical University (Army Military Medical University), Gao Tan Yan Street, Chongqing 400038, China
| | - Yu Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Proteomics Disease, Institute of Burn Research, Southwest Hospital (the First Affiliated Hospital), Third Military Medical University (Army Military Medical University), Gao Tan Yan Street, Chongqing 400038, China
| | - Bo You
- State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Proteomics Disease, Institute of Burn Research, Southwest Hospital (the First Affiliated Hospital), Third Military Medical University (Army Military Medical University), Gao Tan Yan Street, Chongqing 400038, China.,Department of Burn and Plastic Surgery, No. 958 Hospital of Army, Southwest Hospital, Third Military Medical University (Army Military Medical University), Jian Xin Dong Street, Chongqing 400020, China
| | - Yuan Peng
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Zhi Zao Ju Road, Shanghai 200011, China
| | - Yajie Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Proteomics Disease, Institute of Burn Research, Southwest Hospital (the First Affiliated Hospital), Third Military Medical University (Army Military Medical University), Gao Tan Yan Street, Chongqing 400038, China
| | - Zichen Yang
- State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Proteomics Disease, Institute of Burn Research, Southwest Hospital (the First Affiliated Hospital), Third Military Medical University (Army Military Medical University), Gao Tan Yan Street, Chongqing 400038, China
| | - Yixin Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Zhi Zao Ju Road, Shanghai 200011, China
| | - Jing Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Proteomics Disease, Institute of Burn Research, Southwest Hospital (the First Affiliated Hospital), Third Military Medical University (Army Military Medical University), Gao Tan Yan Street, Chongqing 400038, China
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21
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Panigrahi T, D'Souza S, Shetty R, Padmanabhan Nair A, Ghosh A, Jacob Remington Nelson E, Ghosh A, Sethu S. Genistein-Calcitriol Mitigates Hyperosmotic Stress-Induced TonEBP, CFTR Dysfunction, VDR Degradation and Inflammation in Dry Eye Disease. Clin Transl Sci 2020; 14:288-298. [PMID: 32896986 PMCID: PMC7877851 DOI: 10.1111/cts.12858] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/30/2020] [Indexed: 01/21/2023] Open
Abstract
Dry eye disease (DED) signs and symptoms are causally associated with increased ocular surface (OS) inflammation. Modulation of key regulators of aberrant OS inflammation is of interest for clinical management. We investigated the status and the potential to harness key endogenous protective factors, such as cystic fibrosis transmembrane conductance regulator (CFTR) and vitamin D receptor (VDR) in hyperosmotic stress‐associated inflammation in patients with DED and in vitro. Conjunctival impression cytology samples from control subjects (n = 11) and patients with DED (n = 15) were used to determine the status of hyperosmotic stress (TonEBP/NFAT5), inflammation (IL‐6, IL‐8, IL‐17A/F, TNFα, MMP9, and MCP1), VDR, and intracellular chloride ion (GLRX5) by quantitative polymerase chain reaction and/or immunofluorescence. Human corneal epithelial cells (HCECs) were used to study the effect of CFTR activator (genistein) and vitamin D (calcitriol) in hyperosmotic stress (HOs)‐induced response in vitro. Western blotting was used to determine the expression of these proteins, along with p‐p38. Significantly, higher expression of inflammatory factors, TonEBP, GLRX5, and reduced VDR were observed in patients with DED and in HOs‐induced HCECs in vitro. Expression of TonEBP positively correlated with expression of inflammatory genes in DED. Increased TonEBP and GLRX5 provides confirmation of osmotic stress and chloride ion imbalance in OS epithelium in DED. These along with reduced VDR suggests dysregulated OS homeostasis in DED. Combination of genistein and calcitriol reduced HOs‐induced TonEBP, inflammatory gene expression, and p‐p38, and abated VDR degradation in HCECs. Henceforth, this combination should be further explored for its relevance in the management of DED.
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Affiliation(s)
- Trailokyanath Panigrahi
- GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India.,Gene Therapy Laboratory, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Sharon D'Souza
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India
| | - Rohit Shetty
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India
| | - Archana Padmanabhan Nair
- GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India.,Manipal Academy of Higher Education, Manipal, India
| | - Anuprita Ghosh
- GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India
| | - Everette Jacob Remington Nelson
- Gene Therapy Laboratory, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Arkasubhra Ghosh
- GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India.,Singapore Eye Research Institute, Singapore, Singapore
| | - Swaminathan Sethu
- GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India
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22
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Scott P, Anderson K, Singhania M, Cormier R. Cystic Fibrosis, CFTR, and Colorectal Cancer. Int J Mol Sci 2020; 21:2891. [PMID: 32326161 PMCID: PMC7215855 DOI: 10.3390/ijms21082891] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/17/2020] [Accepted: 04/19/2020] [Indexed: 02/06/2023] Open
Abstract
Cystic fibrosis (CF), caused by biallelic inactivating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, has recently been categorized as a familial colorectal cancer (CRC) syndrome. CF patients are highly susceptible to early, aggressive colorectal tumor development. Endoscopic screening studies have revealed that by the age of forty 50% of CF patients will develop adenomas, with 25% developing aggressive advanced adenomas, some of which will have already advanced to adenocarcinomas. This enhanced risk has led to new CF colorectal cancer screening recommendations, lowering the initiation of endoscopic screening to age forty in CF patients, and to age thirty in organ transplant recipients. The enhanced risk for CRC also extends to the millions of people (more than 10 million in the US) who are heterozygous carriers of CFTR gene mutations. Further, lowered expression of CFTR is reported in sporadic CRC, where downregulation of CFTR is associated with poor survival. Mechanisms underlying the actions of CFTR as a tumor suppressor are not clearly understood. Dysregulation of Wnt/β-catenin signaling and disruption of intestinal stem cell homeostasis and intestinal barrier integrity, as well as intestinal dysbiosis, immune cell infiltration, stress responses, and intestinal inflammation have all been reported in human CF patients and in animal models. Notably, the development of new drug modalities to treat non-gastrointestinal pathologies in CF patients, especially pulmonary disease, offers hope that these drugs could be repurposed for gastrointestinal cancers.
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Affiliation(s)
| | | | | | - Robert Cormier
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA; (P.S.); (K.A.); (M.S.)
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23
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The role of endothelial cells in cystic fibrosis. J Cyst Fibros 2019; 18:752-761. [DOI: 10.1016/j.jcf.2019.07.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 06/18/2019] [Accepted: 07/23/2019] [Indexed: 12/22/2022]
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24
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Anderson KJ, Cormier RT, Scott PM. Role of ion channels in gastrointestinal cancer. World J Gastroenterol 2019; 25:5732-5772. [PMID: 31636470 PMCID: PMC6801186 DOI: 10.3748/wjg.v25.i38.5732] [Citation(s) in RCA: 134] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 07/26/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023] Open
Abstract
In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell. The functions of ion channels in the gastrointestinal (GI) tract influence a variety of cellular processes, many of which overlap with these hallmarks of cancer. In this review we focus on the roles of the calcium (Ca2+), sodium (Na+), potassium (K+), chloride (Cl-) and zinc (Zn2+) transporters in GI cancer, with a special emphasis on the roles of the KCNQ1 K+ channel and CFTR Cl- channel in colorectal cancer (CRC). Ca2+ is a ubiquitous second messenger, serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle, apoptosis, and migration. Various members of the TRP superfamily, including TRPM8, TRPM7, TRPM6 and TRPM2, have been implicated in GI cancers, especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer. Voltage-gated sodium channels (VGSCs) are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells. The VGSC NaV1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples. Studies have demonstrated that conductance through NaV1.5 contributes significantly to CRC cell invasiveness and cancer progression. Zn2+ transporters of the ZIP/SLC39A and ZnT/SLC30A families are dysregulated in all major GI organ cancers, in particular, ZIP4 up-regulation in pancreatic cancer (PC). More than 70 K+ channel genes, clustered in four families, are found expressed in the GI tract, where they regulate a range of cellular processes, including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract. Several distinct types of K+ channels are found dysregulated in the GI tract. Notable are hERG1 upregulation in PC, gastric cancer (GC) and CRC, leading to enhanced cancer angiogenesis and invasion, and KCNQ1 down-regulation in CRC, where KCNQ1 expression is associated with enhanced disease-free survival in stage II, III, and IV disease. Cl- channels are critical for a range of cellular and tissue processes in the GI tract, especially fluid balance in the colon. Most notable is CFTR, whose deficiency leads to mucus blockage, microbial dysbiosis and inflammation in the intestinal tract. CFTR is a tumor suppressor in several GI cancers. Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC. Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels (CLIC1, 3 & 4) and the chloride channel accessory proteins (CLCA1,2,4). CLIC1 & 4 are upregulated in PC, GC, gallbladder cancer, and CRC, while the CLCA proteins have been reported to be down-regulated in CRC. In summary, it is clear, from the diverse influences of ion channels, that their aberrant expression and/or activity can contribute to malignant transformation and tumor progression. Further, because ion channels are often localized to the plasma membrane and subject to multiple layers of regulation, they represent promising clinical targets for therapeutic intervention including the repurposing of current drugs.
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Affiliation(s)
- Kyle J Anderson
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
| | - Robert T Cormier
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
| | - Patricia M Scott
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
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25
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Liou TG. The Clinical Biology of Cystic Fibrosis Transmembrane Regulator Protein: Its Role and Function in Extrapulmonary Disease. Chest 2018; 155:605-616. [PMID: 30359614 DOI: 10.1016/j.chest.2018.10.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 10/08/2018] [Accepted: 10/10/2018] [Indexed: 02/07/2023] Open
Abstract
Normal cystic fibrosis (CF) transmembrane regulator (CFTR) protein has multiple functions in health and disease. Many mutations in the CFTR gene produce abnormal or absent protein. CFTR protein dysfunction underlies the classic CF phenotype of progressive pulmonary and GI pathology but may underlie diseases not usually associated with CF. This review highlights selected extrapulmonary disease that may be associated with abnormal CFTR. Increasing survival in CF is associated with increasing incidence of diseases associated with aging. CFTR dysfunction in older individuals may have novel effects on glucose metabolism, control of insulin release, regulation of circadian rhythm, and cancer cell pathophysiology. In individuals who have cancers with acquired CFTR suppression, their tumors may more likely exhibit rapid expansion, epithelial-to-mesenchymal transformation, abnormally reduced apoptosis, and increased metastatic potential. The new modulators of CFTR protein synthesis could facilitate the additional exploration needed to better understand the unfolding clinical biology of CFTR in human disease, even as they revolutionize treatment of patients with CF.
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Affiliation(s)
- Theodore G Liou
- Center for Quantitative Biology, The Adult Cystic Fibrosis Center and the Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT.
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26
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Jaudszus A, Arnold C, Hentschel J, Hünniger K, Baier M, Mainz JG. Increased cytokines in cystic fibrosis patients' upper airways during a new P. aeruginosa colonization. Pediatr Pulmonol 2018; 53:881-887. [PMID: 29624919 DOI: 10.1002/ppul.24004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 03/14/2018] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Previously, we found linkages of inflammatory mediator levels in CF upper airways (UAW) sampled by nasal lavage (NL) to disease severity and to chronic pathogen colonization such as Pseudomonas aeruginosa (PsA). Here, we assess UAW cytokine dynamics in CF patients with a new PsA colonization. METHODS We measured cytokines in 149 longitudinally obtained NL samples from 34 CF patients. Cytokine concentrations determined prior to, at the time of de novo PsA detection in either UAW or lower airways (LAW), and in a subsequent PsA free period in newly colonized patients (PsA-new/n = 7) were compared to levels of not- (PsA-free/n = 13) and chronically colonized patients (PsA-chron/n = 14). Moreover, serological and clinical data were compiled. RESULTS Concentrations of IL-1ß, IL-6, and IL-8 in samples taken prior to new PsA detection were comparable with PsA-free patients. At the time of PsA detection and, most interestingly, irrespective of whether PsA occurred in the UAW or LAW, IL-8 increased (P = 0.009) and IL-6 tended to increase (P = 0.081). In these patients, detection of PsA was not related to elevated PsA antibody-titers. In comparison, NL of PsA-chron patients revealed generally lower IL-8 and IL-1β concentrations as in PsA-free patients, most likely due to a consequent antibiotic and anti-inflammatory therapy (eg, with azithromycin). CONCLUSIONS Monitoring cytokine dynamics in the UAW by serial NL sampling may be valuable in the early phase of PsA acquisition and, thus, increase the chance to adjust treatment options early and more specifically.
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Affiliation(s)
| | | | - Julia Hentschel
- Jena University Hospital, CF-Center, Jena, Germany.,Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany
| | - Kerstin Hünniger
- Septomics Research Center, Leibniz Institute for Natural Product Research and Infection Biology- Hans-Knoell-Institute and Friedrich Schiller University, Jena, Germany
| | - Michael Baier
- Jena University Hospital, Department of Medical Microbiology, Jena, Germany
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27
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Philp AR, Riquelme TT, Millar-Büchner P, González R, Sepúlveda FV, Cid LP, Flores CA. Kcnn4 is a modifier gene of intestinal cystic fibrosis preventing lethality in the Cftr-F508del mouse. Sci Rep 2018; 8:9320. [PMID: 29915289 PMCID: PMC6006244 DOI: 10.1038/s41598-018-27465-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 06/04/2018] [Indexed: 02/07/2023] Open
Abstract
Nearly 70% of cystic fibrosis (CF) patients bear the phenylalanine-508 deletion but disease severity differs greatly, and is not explained by the existence of different mutations in compound heterozygous. Studies demonstrated that genes other than CFTR relate to intestinal disease in humans and CF-mouse. Kcnn4, the gene encoding the calcium-activated potassium channel KCa3.1, important for intestinal secretion, is present in a locus linked with occurrence of intestinal CF-disease in mice and humans. We reasoned that it might be a CF-modifier gene and bred a CF-mouse with Kcnn4 silencing, finding that lethality was almost abolished. Silencing of Kcnn4 did not improve intestinal secretory functions, but rather corrected increased circulating TNF-α level and reduced intestinal mast cell increase. Given the importance of mast cells in intestinal disease additional double mutant CF-animals were tested, one lacking mast cells (C-kitW-sh/W-sh) and Stat6-/- to block IgE production. While mast cell depletion had no effect, silencing Stat6 significantly reduced lethality. Our results show that Kcnn4 is an intestinal CF modifier gene partially acting through a STAT6-dependent mechanism.
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Affiliation(s)
- Amber R Philp
- Centro de Estudios Científicos (CECs), Arturo Prat 514, Valdivia, Chile
- Universidad Austral de Chile, Valdivia, Chile
| | - Texia T Riquelme
- Centro de Estudios Científicos (CECs), Arturo Prat 514, Valdivia, Chile
| | - Pamela Millar-Büchner
- Centro de Estudios Científicos (CECs), Arturo Prat 514, Valdivia, Chile
- Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany
| | - Rodrigo González
- Centro de Estudios Científicos (CECs), Arturo Prat 514, Valdivia, Chile
| | | | - L Pablo Cid
- Centro de Estudios Científicos (CECs), Arturo Prat 514, Valdivia, Chile
| | - Carlos A Flores
- Centro de Estudios Científicos (CECs), Arturo Prat 514, Valdivia, Chile.
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28
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Kanhere M, Chassaing B, Gewirtz AT, Tangpricha V. Role of vitamin D on gut microbiota in cystic fibrosis. J Steroid Biochem Mol Biol 2018; 175:82-87. [PMID: 27818276 PMCID: PMC5415426 DOI: 10.1016/j.jsbmb.2016.11.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Revised: 10/24/2016] [Accepted: 11/01/2016] [Indexed: 02/07/2023]
Abstract
This review explores the potential for vitamin D to favorably alter the gut microbiota, given emerging evidence of the role of vitamin D in controlling mucosal inflammation in the gut. It will focus on cystic fibrosis (CF) patients, a population with both vitamin D deficiency due to gut malabsorption and an altered gut microbiota composition. Recent evidence shows that vitamin D acts to maintain the integrity of the gut mucosal barrier by enhancement of intercellular junctions that control mucosal permeability and reduction of pro-inflammatory cytokines such as IL-8. In addition, vitamin D receptor-mediated signaling has been shown to inhibit inflammation-induced apoptosis of intestinal epithelial cells. As a result of these effects on the intestinal mucosa, maintenance of sufficient vitamin D status may be essential for the development of a healthy gut microbiota, particularly in conditions defined by chronic mucosal inflammation such as CF. We hypothesize here that high dose vitamin D may be used to favorably manipulate the aberrant mucosa seen in patients with CF. This may result in improved clinical outcomes in association with a low inflammatory environment that allows beneficial bacteria to outcompete opportunistic pathogens. Current evidence is sparse but encouraging, and additional evidence is needed to establish vitamin D as a therapeutic approach for gut microbiota modification.
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Affiliation(s)
- Mansi Kanhere
- Division of Endocrinology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Benoit Chassaing
- Center for Inflammation, Immunity, & Infection, Institute for Biomedical Sciences, Georgia State University, USA
| | - Andrew T Gewirtz
- Center for Inflammation, Immunity, & Infection, Institute for Biomedical Sciences, Georgia State University, USA
| | - Vin Tangpricha
- Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA; Atlanta VA Medical Center, Decatur, GA, USA.
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29
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Hohwieler M, Perkhofer L, Liebau S, Seufferlein T, Müller M, Illing A, Kleger A. Stem cell-derived organoids to model gastrointestinal facets of cystic fibrosis. United European Gastroenterol J 2017; 5:609-624. [PMID: 28815024 PMCID: PMC5548342 DOI: 10.1177/2050640616670565] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Accepted: 08/25/2016] [Indexed: 12/16/2022] Open
Abstract
Cystic fibrosis (CF) is one of the most frequently occurring inherited human diseases caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) which lead to ample defects in anion transport and epithelial fluid secretion. Existing models lack both access to early stages of CF development and a coeval focus on the gastrointestinal CF phenotypes, which become increasingly important due increased life span of the affected individuals. Here, we provide a comprehensive overview of gastrointestinal facets of CF and the opportunity to model these in various systems in an attempt to understand and treat CF. A particular focus is given on forward-leading organoid cultures, which may circumvent current limitations of existing models and thereby provide a platform for drug testing and understanding of disease pathophysiology in gastrointestinal organs.
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Affiliation(s)
- Meike Hohwieler
- Department of Internal Medicine 1, University Medical Centre Ulm, Ulm, Germany
| | - Lukas Perkhofer
- Department of Internal Medicine 1, University Medical Centre Ulm, Ulm, Germany
| | - Stefan Liebau
- Institute of Neuroanatomy, Eberhard Karls University Tuebingen, Oesterbergstr. 3, 72074 Tuebingen, Germany
| | - Thomas Seufferlein
- Department of Internal Medicine 1, University Medical Centre Ulm, Ulm, Germany
| | - Martin Müller
- Department of Internal Medicine 1, University Medical Centre Ulm, Ulm, Germany
| | - Anett Illing
- Department of Internal Medicine 1, University Medical Centre Ulm, Ulm, Germany
| | - Alexander Kleger
- Department of Internal Medicine 1, University Medical Centre Ulm, Ulm, Germany
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30
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Garg M, Ooi CY. The Enigmatic Gut in Cystic Fibrosis: Linking Inflammation, Dysbiosis, and the Increased Risk of Malignancy. Curr Gastroenterol Rep 2017; 19:6. [PMID: 28155088 DOI: 10.1007/s11894-017-0546-0] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Intestinal inflammation, dysbiosis, and increased gastrointestinal malignancy risks are well-described in patients with cystic fibrosis (CF). However, there is limited understanding of their pathophysiology. This review aims to discuss these issues and assess potential links between them. RECENT FINDINGS Evidence of links between intestinal inflammation and dysbiosis (an imbalance in intestinal microbial populations) exist. Recent studies have demonstrated reduction in intestinal inflammation with probiotic administration. Both bacterial dysbiosis and gut inflammation contribute to the suboptimal nutritional status seen in children with CF. Short-chain fatty acids may be reduced in the gut lumen as a result of bacterial imbalances and may promote inflammation. Inflammation and bacterial dysbiosis in CF may also contribute to emerging adult complications such as gastrointestinal malignancy. An increase in carcinogenic microbes and reduction in microbes protective against cancer have been found in CF, linking bacterial dysbiosis and cancer. Murine studies suggest the CF gene, cystic fibrosis transmembrane conductance regulator (CFTR) gene, itself may be a tumour suppressor gene. The pathophysiology of interactions among intestinal inflammation, dysbiosis, and malignancy in CF is not clearly understood and requires further research.
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Affiliation(s)
- Millie Garg
- School of Women's and Children's Health, Medicine, University of New South Wales, Randwick, NSW, 2031, Australia
| | - Chee Y Ooi
- School of Women's and Children's Health, Medicine, University of New South Wales, Randwick, NSW, 2031, Australia.
- Department of Paediatric Gastroenterology, Sydney Children's Hospital, Randwick, NSW, 2031, Australia.
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31
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Liu K, Zhang X, Zhang JT, Tsang LL, Jiang X, Chan HC. Defective CFTR- β-catenin interaction promotes NF-κB nuclear translocation and intestinal inflammation in cystic fibrosis. Oncotarget 2016; 7:64030-64042. [PMID: 27588407 PMCID: PMC5325423 DOI: 10.18632/oncotarget.11747] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 08/24/2016] [Indexed: 12/31/2022] Open
Abstract
While inflammation with aberrant activation of NF-κB pathway is a hallmark of cystic fibrosis (CF), the molecular mechanisms underlying the link between CFTR defect and activation of NF-κB-mediated pro-inflammatory response remain elusive. Here, we investigated the link between CFTR defect and NF-κB activation in ΔF508cftr-/- mouse intestine and human intestinal epithelial cell lines. Our results show that the NF-κB/COX-2/PGE2 pathway is activated whereas the β-catenin pathway is suppressed in CF mouse intestine and CFTR-knockdown cells. Activation of β-catenin pathway by GSK3 inhibitors suppresses CFTR mutation/knockdown-induced NF-κB/COX-2/PGE2 pathway in ΔF508 mouse intestine and CFTR-knockdown cells. In contrast, suppression of β-catenin signaling induces the nuclear translocation of NF-κB. In addition, CFTR co-localizes and interacts with β-catenin while CFTR mutation disrupts the interaction between NF-κB and β-catenin in mouse intestine. Treatment with proteasome inhibitor MG132 completely reverses the reduced expression of β-catenin in Caco-2 cells. Collectively, these results indicate that CFTR stabilizes β-catenin and prevents its degradation, defect of which results in the activation of NF-κB-mediated inflammatory cascade. The present study has demonstrated a previously unsuspected interaction between CFTR and β-catenin that regulates NF-κB nuclear translocation in mouse intestine. Therefore, our study provides novel insights into the physiological function of CFTR and pathogenesis of CF-related diseases in addition to the NF-κB-mediated intestinal inflammation seen in CF.
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Affiliation(s)
- Kaisheng Liu
- Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Xiaohu Zhang
- Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
- Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Chengdu, PR China
| | - Jie Ting Zhang
- Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Lai Ling Tsang
- Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Xiaohua Jiang
- Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
- School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China
| | - Hsiao Chang Chan
- Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
- School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China
- Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Chengdu, PR China
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32
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Knauf F, Thomson RB, Heneghan JF, Jiang Z, Adebamiro A, Thomson CL, Barone C, Asplin JR, Egan ME, Alper SL, Aronson PS. Loss of Cystic Fibrosis Transmembrane Regulator Impairs Intestinal Oxalate Secretion. J Am Soc Nephrol 2016; 28:242-249. [PMID: 27313231 DOI: 10.1681/asn.2016030279] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 05/16/2016] [Indexed: 11/03/2022] Open
Abstract
Patients with cystic fibrosis have an increased incidence of hyperoxaluria and calcium oxalate nephrolithiasis. Net intestinal absorption of dietary oxalate results from passive paracellular oxalate absorption as modified by oxalate back secretion mediated by the SLC26A6 oxalate transporter. We used mice deficient in the cystic fibrosis transmembrane conductance regulator gene (Cftr) to test the hypothesis that SLC26A6-mediated oxalate secretion is defective in cystic fibrosis. We mounted isolated intestinal tissue from C57BL/6 (wild-type) and Cftr-/- mice in Ussing chambers and measured transcellular secretion of [14C]oxalate. Intestinal tissue isolated from Cftr-/- mice exhibited significantly less transcellular oxalate secretion than intestinal tissue of wild-type mice. However, glucose absorption, another representative intestinal transport process, did not differ in Cftr-/- tissue. Compared with wild-type mice, Cftr-/- mice showed reduced expression of SLC26A6 in duodenum by immunofluorescence and Western blot analysis. Furthermore, coexpression of CFTR stimulated SLC26A6-mediated Cl--oxalate exchange in Xenopus oocytes. In association with the profound defect in intestinal oxalate secretion, Cftr-/- mice had serum and urine oxalate levels 2.5-fold greater than those of wild-type mice. We conclude that defective intestinal oxalate secretion mediated by SLC26A6 may contribute to the hyperoxaluria observed in this mouse model of cystic fibrosis. Future studies are needed to address whether similar mechanisms contribute to the increased risk for calcium oxalate stone formation observed in patients with cystic fibrosis.
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Affiliation(s)
- Felix Knauf
- Departments of Internal Medicine, .,Department of Nephrology and Hypertension, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | | | - John F Heneghan
- Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts.,Department of Medicine, Harvard Medical School, Boston, Massachusetts; and
| | | | | | | | | | - John R Asplin
- Litholink Corporation, Laboratory Corporation of America Holdings, Chicago, Illinois
| | - Marie E Egan
- Pediatrics, and.,Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
| | - Seth L Alper
- Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts.,Department of Medicine, Harvard Medical School, Boston, Massachusetts; and
| | - Peter S Aronson
- Departments of Internal Medicine, .,Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
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33
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Schnúr A, Hegyi P, Rousseau S, Lukacs GL, Veit G. Epithelial Anion Transport as Modulator of Chemokine Signaling. Mediators Inflamm 2016; 2016:7596531. [PMID: 27382190 PMCID: PMC4921137 DOI: 10.1155/2016/7596531] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 05/03/2016] [Accepted: 05/12/2016] [Indexed: 12/16/2022] Open
Abstract
The pivotal role of epithelial cells is to secrete and absorb ions and water in order to allow the formation of a luminal fluid compartment that is fundamental for the epithelial function as a barrier against environmental factors. Importantly, epithelial cells also take part in the innate immune system. As a first line of defense they detect pathogens and react by secreting and responding to chemokines and cytokines, thus aggravating immune responses or resolving inflammatory states. Loss of epithelial anion transport is well documented in a variety of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, pancreatitis, and cholestatic liver disease. Here we review the effect of aberrant anion secretion with focus on the release of inflammatory mediators by epithelial cells and discuss putative mechanisms linking these transport defects to the augmented epithelial release of chemokines and cytokines. These mechanisms may contribute to the excessive and persistent inflammation in many respiratory and gastrointestinal diseases.
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Affiliation(s)
- Andrea Schnúr
- Department of Physiology, McGill University, Montréal, QC, Canada H3G 1Y6
| | - Péter Hegyi
- Institute for Translational Medicine and 1st Department of Medicine, University of Pécs, Pécs 7624, Hungary
- MTA-SZTE Translational Gastroenterology Research Group, Szeged 6720, Hungary
| | - Simon Rousseau
- The Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montréal, QC, Canada H2X 2P2
| | - Gergely L. Lukacs
- Department of Physiology, McGill University, Montréal, QC, Canada H3G 1Y6
- Department of Biochemistry, McGill University, Montréal, QC, Canada H3G 1Y6
- Groupe de Recherche Axé sur la Structure des Protéines (GRASP), McGill University, Montréal, QC, Canada H3G 1Y6
| | - Guido Veit
- Department of Physiology, McGill University, Montréal, QC, Canada H3G 1Y6
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Morin G, Orlando V, St-Martin Crites K, Patey N, Mailhot G. Vitamin D attenuates inflammation in CFTR knockdown intestinal epithelial cells but has no effect in cells with intact CFTR. Am J Physiol Gastrointest Liver Physiol 2016; 310:G539-49. [PMID: 26893158 DOI: 10.1152/ajpgi.00060.2015] [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: 02/26/2015] [Accepted: 01/31/2016] [Indexed: 01/31/2023]
Abstract
The cystic fibrosis (CF) intestine is characterized by chronic inflammation. CF patients are instructed to ingest supplemental vitamin D on a daily basis thereby exposing their intestinal tract to pharmacological amounts of this vitamin. It has been shown that vitamin D exerts intestinal anti-inflammatory properties. We therefore postulate that vitamin D may be beneficial in the management of CF intestinal inflammation by attenuating cellular inflammatory responses. In this study, we investigated the anti-inflammatory effects of the oral form of vitamin D3 (cholecalciferol) and its metabolites, 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3, on cytokine-induced inflammatory responses in intestinal epithelial Caco-2/15 cells with intact expression of CF transmembrane conductance regulator (CFTR) and knockdown for CFTR. We show that 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 inhibited p38MAPK phosphorylation and that these effects were not mediated by changes in the expression of MAPK phosphatase-1 (MKP-1). However, 1,25-dihydroxyvitamin D3 exhibited superior anti-inflammatory effects as it furthermore reduced cytokine-induced NF-κB nuclear translocation and interleukin-8 mRNA stability and secretion. Intriguingly, the anti-inflammatory effects of vitamin D metabolites were only observed in CFTR knockdown cells, which may be explained by alterations in its catabolism associated with changes in CYP24A1 expression. These observations were supported in vivo whereby Cftr(-/-) mice fed large amounts of vitamin D3 for 2 mo led to a reduction in the number of eosinophils and apoptotic cells in the duodenal mucosa of females but not males. Altogether, these findings suggest that vitamin D exerts intestinal anti-inflammatory actions under specific circumstances and may thus prove beneficial in CF.
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Affiliation(s)
- Geneviève Morin
- Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada; and
| | - Valérie Orlando
- Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada; and
| | | | - Natacha Patey
- Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada; and
| | - Geneviève Mailhot
- Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada; and Department of Nutrition, Université de Montréal, Montréal, Quebec, Canada
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