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Kaur P, Karuppuchamy T, Chilukuri A, Kim M, Urrete J, Shen Z, Saxon L, Lundborg LR, Mikulski Z, Jedlicka P, Rivera-Nieves J. S1P Lyase Inhibition Increased Intestinal S1P, Disrupted the Intestinal Barrier and Aggravated DSS-Induced Colitis. Inflamm Bowel Dis 2025:izaf030. [PMID: 39960746 DOI: 10.1093/ibd/izaf030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Indexed: 04/02/2025]
Abstract
BACKGROUND Sphingosine-1-phospate (S1P) receptor agonists (eg, ozanimod) desensitize migrating lymphocytes by irreversibly binding to S1P receptors (S1PR) and triggering their proteasomal degradation. Desensitized lymphocytes cannot sense S1P, therefore, halting lymphocyte recirculation. The S1P lyase (SPL) irreversibly degrades S1P and its inhibition disrupts the S1P gradient. We previously found that systemic SPL inhibitors induce central immunosuppression. Here, we examined whether SPL inhibition may attenuate colitis without systemic immunotoxicity. METHODS We first analyzed SPL expression and localization in mice using qRT-PCR and immunohistochemistry. SPL inhibitors 4-deoxypyridoxine hydrochloride (DOP) and 2-acetyl-4-(tetrahydroxybutyl) imidazole (THI) were used to inhibit SPL systemically, whereas a conditional intestinal epithelial cell (IEC)-specific SPL-deficient mouse was used to evaluate the effects of IEC-specific SPL inhibition on survival, disease activity, histological severity of dextran sulfate sodium-induced colitis, S1P levels, and intestinal permeability. RESULTS Sgpl1 mRNA transcripts and protein were ubiquitously expressed in gastrointestinal (GI) tract leukocytes and IEC. Systemic SPL inhibitors did not induce colitis by themselves but depleted CD4+ and CD8+ T cells from blood. However, contrary to its therapeutic effects on ileitis, systemic inhibition reduced survival, accelerated weight loss, worsened histopathological inflammation indices, and tissue damage. We then examined the effects of IEC-specific inhibition on peripheral cell counts and severity of colitis. We found that while it spared peripheral immunity, it similarly hastened colitis. Finally, we examined whether colitis acceleration was due to epithelial barrier compromise after disruption of the S1P gradient. We found that not only systemic but also IEC-specific SPL inhibition increased local S1P levels and led to IEC barrier compromise. CONCLUSION Homeostatic intestinal S1P levels are critical for the regulation of IEC barrier function. Further studies using adaptive immunity-based inflammatory bowel diseases (IBD) models are required to assess the translational value of IEC-specific SPL inhibition as a therapeutic target for human IBD.
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Affiliation(s)
- Prabhdeep Kaur
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
| | - Thangaraj Karuppuchamy
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
| | - Amruth Chilukuri
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
| | - Margaret Kim
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
| | - Josef Urrete
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
| | - Zining Shen
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
| | - Leo Saxon
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
| | - Luke R Lundborg
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
| | - Zbigniew Mikulski
- Histology and Microscopy Core, La Jolla Institute for Immunology, La Jolla, CA, USA
| | - Paul Jedlicka
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Jesús Rivera-Nieves
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
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Kitsou K, Kokkotis G, Rivera-Nieves J, Bamias G. Targeting the Sphingosine-1-Phosphate Pathway: New Opportunities in Inflammatory Bowel Disease Management. Drugs 2024; 84:1179-1197. [PMID: 39322927 PMCID: PMC12057646 DOI: 10.1007/s40265-024-02094-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2024] [Indexed: 09/27/2024]
Abstract
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC) are chronic immune-mediated diseases which primarily target the intestines. In recent years, the development and regulatory approval of various immunotherapies, both biological agents and small molecules, that target specific pathways of the IBD-associated inflammatory cascade have revolutionized the treatment of IBD. Small molecules offer the advantages of oral administration and short wash-out times. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of ceramide, which exerts its functions after binding to five G-protein-coupled receptors (S1PR1-S1PR5). Concerning IBD, S1P participates in the egress of lymphocytes from the secondary lymphoid tissue and their re-circulation to sites of inflammation, mainly through S1PR1 binding. In addition, this system facilitates the differentiation of T-helper cells towards proinflammatory immunophenotypes. Recently, S1P modulators have offered a valuable addition to the IBD treatment armamentarium. They exert their anti-inflammatory function via sequestration of T cell subsets in the lymphoid tissues and prevention of gut homing. In this review, we revisit the role of the S1P/S1PR axis in the pathogenesis of IBD and discuss efficacy and safety data from clinical trials and real-world reports on the two S1PR modulators, ozanimod and etrasimod, that are currently approved for IBD treatment, and comment on their potential positioning in the IBD day-to-day management. We also present recent data on emerging S1P modulators. Finally, based on the successes and failures of S1PR modulators in IBD, we discuss future avenues of IBD treatments targeting the S1P/S1PR axis.
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Affiliation(s)
| | - Georgios Kokkotis
- GI-Unit, 3rd Department of Internal Medicine, Sotiria Hospital, 152 Mesogeion Av., 11528, Athens, Greece
| | - Jesús Rivera-Nieves
- San Diego VA Medical Center (SDVAMC), San Diego, CA, USA
- Division of Gastroenterology, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, USA
| | - Giorgos Bamias
- GI-Unit, 3rd Department of Internal Medicine, Sotiria Hospital, 152 Mesogeion Av., 11528, Athens, Greece.
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George N, Xiao J. Inhibiting sphingosine 1-phosphate lyase: From efficacy to mechanism. Neurobiol Dis 2024; 199:106585. [PMID: 38955289 DOI: 10.1016/j.nbd.2024.106585] [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: 06/06/2024] [Revised: 06/28/2024] [Accepted: 06/28/2024] [Indexed: 07/04/2024] Open
Abstract
Sphingosine-1 phosphate (S1P) is a lipid metabolite regulating diverse biological processes, including proliferation, differentiation, migration, and apoptosis, highlighting its physiological and therapeutic significance. Current S1P-based therapeutic approaches primarily focus on modulating the downstream signalling via targeting S1P receptors, however, this is challenged by incomplete receptor internalisation. Sphingosine-1-phosphate lyase (SPL) is a highly conserved enzyme that "gatekeeps" the final step of S1P degradation. Cognisant of the complex ligand and receptor interaction and dynamic metabolic networks, the selective modulation of SPL activity presents a new opportunity to regulate S1P biosynthesis and reveal its role in various systems. Over the past decade, an evolving effort has been made to identify new molecules that could block SPL activity in vitro or in vivo. This review focuses on summarising the current understanding of the reported SPL inhibitors identified through various screening approaches, discussing their efficacy in diverse model systems and the possible mechanism of action. Whilst effective modulation of S1P levels via inhibiting SPL is feasible, the specificity of those inhibitors remains inconclusive, presenting a clear challenge for future implications. Yet, none of the currently available SPL inhibitors is proven effective in elevating S1P levels within the central nervous system. This review article embraces future research focusing on investigating selective SPL inhibitors with high potency and possibly blood-brain-barrier permeability, which would aid the development of new S1P-based therapeutics for neurological disorders.
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Affiliation(s)
- Nelson George
- Department of Health Sciences and Biostatistics, School of Health Sciences, Swinburne University of Technology, Hawthorn, Victoria, Australia
| | - Junhua Xiao
- Department of Health Sciences and Biostatistics, School of Health Sciences, Swinburne University of Technology, Hawthorn, Victoria, Australia.
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Doll CL, Snider AJ. The diverse roles of sphingolipids in inflammatory bowel disease. FASEB J 2024; 38:e23777. [PMID: 38934445 PMCID: PMC467036 DOI: 10.1096/fj.202400830r] [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: 04/16/2024] [Revised: 05/28/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024]
Abstract
The incidence of inflammatory bowel disease (IBD) has increased over the last 20 years. A variety of causes, both physiological and environmental, contribute to the initiation and progression of IBD, making disease management challenging. Current treatment options target various aspects of the immune response to dampen intestinal inflammation; however, their effectiveness at retaining remission, their side effects, and loss of response from patients over time warrant further investigation. Finding a common thread within the multitude causes of IBD is critical in developing robust treatment options. Sphingolipids are evolutionary conserved bioactive lipids universally generated in all cell types. This diverse lipid family is involved in a variety of fundamental, yet sometimes opposing, processes such as proliferation and apoptosis. Implicated as regulators in intestinal diseases, sphingolipids are a potential cornerstone in understanding IBD. Herein we will describe the role of host- and microbial-derived sphingolipids as they relate to the many factors of intestinal health and IBD.
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Affiliation(s)
- Chelsea L. Doll
- School of Nutritional Sciences and Wellness, University of Arizona, Tucson, AZ 85721, USA
| | - Ashley J. Snider
- School of Nutritional Sciences and Wellness, University of Arizona, Tucson, AZ 85721, USA
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA
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Neri B, Mancone R, Fiorillo M, Schiavone SC, De Cristofaro E, Migliozzi S, Biancone L. Comprehensive overview of novel chemical drugs for ulcerative colitis: focusing on phase 3 and beyond. Expert Opin Pharmacother 2024; 25:485-499. [PMID: 38591242 DOI: 10.1080/14656566.2024.2339926] [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: 02/11/2024] [Accepted: 04/03/2024] [Indexed: 04/10/2024]
Abstract
INTRODUCTION Despite the growing number of highly efficacious biologics and chemical drugs for ulcerative colitis (UC), steroid-free disease control is still difficult to achieve in subgroups of patients due to refractoriness, adverse events, primary or secondary failure. New treatments are therefore still required in order to optimize clinical management of patients with UC. AREAS COVERED The efficacy and safety of both currently available and newly developed small molecules have been summarized. The PubMed database and clinicaltrials.gov were considered in order to search for phase 2b and 3 trials on new chemical drugs for UC. The study drugs reviewed included Janus kinases (JAK) and sphingosine-1-phosphate receptor (S1Pr) inhibitors, α4 integrin antagonist, and micro-RNA-124 upregulators. EXPERT OPINION Rapidity of onset, low immunogenicity, and safety are the main characteristics of small molecules currently available or under evaluation for treatment patients with UC. Among the currently available chemical drugs, the selective JAK and the S1Pr inhibitors are characterized by a good safety profile combined with the ability to induce clinical remission in UC. A relatively low frequency of endoscopic improvement and healing currently appears associated with their use, being higher in UC patients treated with S1Pr inhibitor Etrasimod. Overall, additional new safe and effective drugs are still required in order to optimize disease control in a larger majority of UC patients.
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Affiliation(s)
- Benedetto Neri
- Department of Systems Medicine, Gastroenterological Unit, University "Tor Vergata" of Rome, Rome, Italy
| | - Roberto Mancone
- Department of Systems Medicine, Gastroenterological Unit, University "Tor Vergata" of Rome, Rome, Italy
| | - Mariasofia Fiorillo
- Department of Systems Medicine, Gastroenterological Unit, University "Tor Vergata" of Rome, Rome, Italy
| | - Sara Concetta Schiavone
- Department of Systems Medicine, Gastroenterological Unit, University "Tor Vergata" of Rome, Rome, Italy
| | - Elena De Cristofaro
- Department of Systems Medicine, Gastroenterological Unit, University "Tor Vergata" of Rome, Rome, Italy
| | - Stefano Migliozzi
- Department of Systems Medicine, Gastroenterological Unit, University "Tor Vergata" of Rome, Rome, Italy
| | - Livia Biancone
- Department of Systems Medicine, Gastroenterological Unit, University "Tor Vergata" of Rome, Rome, Italy
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Ya'ar Bar S, Pintel N, Abd Alghne H, Khattib H, Avni D. The therapeutic potential of sphingolipids for cardiovascular diseases. Front Cardiovasc Med 2023; 10:1224743. [PMID: 37608809 PMCID: PMC10440740 DOI: 10.3389/fcvm.2023.1224743] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 07/17/2023] [Indexed: 08/24/2023] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide and Inflammation plays a critical role in the development of CVD. Despite considerable progress in understanding the underlying mechanisms and various treatment options available, significant gaps in therapy necessitate the identification of novel therapeutic targets. Sphingolipids are a family of lipids that have gained attention in recent years as important players in CVDs and the inflammatory processes that underlie their development. As preclinical studies have shown that targeting sphingolipids can modulate inflammation and ameliorate CVDs, targeting sphingolipids has emerged as a promising therapeutic strategy. This review discusses the current understanding of sphingolipids' involvement in inflammation and cardiovascular diseases, the existing therapeutic approaches and gaps in therapy, and explores the potential of sphingolipids-based drugs as a future avenue for CVD treatment.
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Affiliation(s)
- Sapir Ya'ar Bar
- Department of Natural Compound, Nutrition, and Health, MIGAL, Kiryat Shmona, Israel
| | - Noam Pintel
- Department of Natural Compound, Nutrition, and Health, MIGAL, Kiryat Shmona, Israel
| | - Hesen Abd Alghne
- Department of Natural Compound, Nutrition, and Health, MIGAL, Kiryat Shmona, Israel
- Tel-Hai College Department of Biotechnology, Kiryat Shmona, Israel
| | - Hamdan Khattib
- Department of Natural Compound, Nutrition, and Health, MIGAL, Kiryat Shmona, Israel
- Department of Gastroenterology and Hepatology, Tel Aviv University Sackler Faculty of Medicine, Tel Aviv, Israel
| | - Dorit Avni
- Department of Natural Compound, Nutrition, and Health, MIGAL, Kiryat Shmona, Israel
- Tel-Hai College Department of Biotechnology, Kiryat Shmona, Israel
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7
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Zou F, Wang S, Xu M, Wu Z, Deng F. The role of sphingosine-1-phosphate in the gut mucosal microenvironment and inflammatory bowel diseases. Front Physiol 2023; 14:1235656. [PMID: 37560160 PMCID: PMC10407793 DOI: 10.3389/fphys.2023.1235656] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 07/17/2023] [Indexed: 08/11/2023] Open
Abstract
Sphingosine-1-phosphate (S1P), a type of bioactive sphingolipid, can regulate various cellular functions of distinct cell types in the human body. S1P is generated intracellularly by the catalysis of sphingosine kinase 1/2 (SphK1/2). S1P is transferred to the extracellular environment via the S1P transporter, binds to cellular S1P receptors (S1PRs) and subsequently activates S1P-S1PR downstream signaling. Dysbiosis of the intestinal microbiota, immune dysregulation and damage to epithelial barriers are associated with inflammatory bowel disease (IBD). Generally, S1P mainly exerts a proinflammatory effect by binding to S1PR1 on lymphocytes to facilitate lymphocyte migration to inflamed tissues, and increased S1P was found in the intestinal mucosa of IBD patients. Notably, there is an interaction between the distribution of gut bacteria and SphK-S1P signaling in the intestinal epithelium. S1P-S1PR signaling can also regulate the functions of intestinal epithelial cells (IECs) in mucosa, including cell proliferation and apoptosis. Additionally, increased S1P in immune cells of the lamina propria aggravates the inflammatory response by increasing the production of proinflammatory cytokines. Several novel drugs targeted at S1PRs have recently been used for IBD treatment. This review provides an overview of the S1P-S1PR signaling pathway and, in particular, summarizes the various roles of S1P in the gut mucosal microenvironment to deeply explore the function of S1P-S1PR signaling during intestinal inflammation and, more importantly, to identify potential therapeutic targets for IBD in the SphK-S1P-S1PR axis.
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Affiliation(s)
- Fei Zou
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Su Wang
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Mengmeng Xu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Zengrong Wu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Feihong Deng
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
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Liu J, Di B, Xu LL. Recent advances in the treatment of IBD: Targets, mechanisms and related therapies. Cytokine Growth Factor Rev 2023; 71-72:1-12. [PMID: 37455149 DOI: 10.1016/j.cytogfr.2023.07.001] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/08/2023] [Accepted: 07/10/2023] [Indexed: 07/18/2023]
Abstract
Inflammatory bowel disease (IBD), as a representative inflammatory disease, currently has multiple effective treatment options available and new therapeutic strategies are being actively explored to further increase the treatment options for patients with IBD. Furthermore, biologic agents and small molecule drugs developed for ulcerative colitis (UC) and Crohn's disease (CD) have evolved toward fewer side effects and more accurate targeting. Novel inhibitors that target cytokines (such as IL-12/23 inhibitors, PDE4 inhibitors), integrins (such as integrin inhibitors), cytokine signaling pathways (such as JAK inhibitors, SMAD7 blocker) and cell signaling receptors (such as S1P receptor modulator) have become the preferred treatment choice for many IBD patients. Conventional therapies such as 5-aminosalicylic acid, corticosteroids, immunomodulators and anti-tumor necrosis factor agents continue to demonstrate therapeutic efficacy, particularly in combination with drug therapy. This review integrates research from chemical, biological and adjuvant therapies to evaluate current and future IBD therapies, highlighting the mechanism of action of each therapy and emphasizing the potential of development prospects.
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Affiliation(s)
- Juan Liu
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Bin Di
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.
| | - Li-Li Xu
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.
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Wieczorek I, Strosznajder RP. Recent Insight into the Role of Sphingosine-1-Phosphate Lyase in Neurodegeneration. Int J Mol Sci 2023; 24:ijms24076180. [PMID: 37047151 PMCID: PMC10093903 DOI: 10.3390/ijms24076180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 03/14/2023] [Accepted: 03/15/2023] [Indexed: 04/14/2023] Open
Abstract
Sphingosine-1-phosphate lyase (SPL) is a pyridoxal 5'-phosphate-dependent enzyme involved in the irreversible degradation of sphingosine-1-phosphate (S1P)-a bioactive sphingolipid that modulates a broad range of biological processes (cell proliferation, migration, differentiation and survival; mitochondrial functioning; and gene expression). Although SPL activity leads to a decrease in the available pool of S1P in the cell, at the same time, hexadecenal and phosphoethanolamine, compounds with potential biological activity, are generated. The increased expression and/or activity of SPL, and hence the imbalance between S1P and the end products of its cleavage, were demonstrated in several pathological states. On the other hand, loss-of-function mutations in the SPL encoding gene are a cause of severe developmental impairments. Recently, special attention has been paid to neurodegenerative diseases as the most common pathologies of the nervous system. This review summarizes the current findings concerning the role of SPL in the nervous system with an emphasis on neurodegeneration. Moreover, it briefly discusses pharmacological compounds directed to inhibit its activity.
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Affiliation(s)
- Iga Wieczorek
- Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego 5 St., 02-106 Warsaw, Poland
| | - Robert Piotr Strosznajder
- Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego 5 St., 02-106 Warsaw, Poland
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Zundler S, Schulze LL, Neurath MF. Controlling in and out - the future of interfering with immune cell trafficking in inflammatory bowel disease. Expert Rev Clin Immunol 2023; 19:155-167. [PMID: 36427088 DOI: 10.1080/1744666x.2023.2152794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Immune cell trafficking is a key requirement in the pathogenesis of inflammatory bowel diseases. Consistently, therapeutic strategies to target immune cell trafficking have been established and continue to be developed for the treatment of ulcerative colitis and Crohn's disease. AREAS COVERED In this review, we briefly summarize the most important checkpoints of intestinal immune cell trafficking and their importance during IBD. Moreover, we provide an overview of associated therapeutic targets and previous as well as current efforts on treatment strategies related to these targets. EXPERT OPINION Finally, we comment on potential future developments that might shape the field of immune cell trafficking in the context of IBD.
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Affiliation(s)
- Sebastian Zundler
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Lisa Lou Schulze
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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11
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Tourkochristou E, Mouzaki A, Triantos C. Unveiling the biological role of sphingosine-1-phosphate receptor modulators in inflammatory bowel diseases. World J Gastroenterol 2023; 29:110-125. [PMID: 36683721 PMCID: PMC9850947 DOI: 10.3748/wjg.v29.i1.110] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/16/2022] [Accepted: 12/14/2022] [Indexed: 01/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide. The increasing disease burden worldwide, lack of response to current biologic therapeutics, and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy. Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics. Sphingosine-1-phosphate (S1P) receptor (S1PR) modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement. S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival, differentiation, migration, proliferation, immune response, and lymphocyte trafficking. T lymphocytes play an important role in regulating inflammatory responses. In inflamed IBD tissue, an imbalance between T helper (Th) and regulatory T lymphocytes and Th cytokine levels was found. The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD. S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking, lymphocyte number, lymphocyte activity, cytokine production, and contributing to gut barrier function.
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Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
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Sun Y, Cheng G, Du L, Gan Y, Li B, Yan S, Shao M, Jin H, Li S. Chuanzhitongluo capsule ameliorates microcirculatory dysfunction in rats: Efficacy evaluation and metabolic profiles. Front Pharmacol 2022; 13:1011333. [PMID: 36278210 PMCID: PMC9585327 DOI: 10.3389/fphar.2022.1011333] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 09/20/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Ischemic stroke is a leading cause of mortality and disability worldwide. Microcirculatory dysfunction is the foremost hindrance for a good clinical prognosis in ischemic stroke patients. Clinical researches show that Chuanzhitongluo capsule (CZTL) has a curative effect during the recovery period of ischemic stroke, which contributes to a good prognosis. However, it is not known whether CZTL treats ischemic stroke by ameliorating microcirculation dysfunction. Objective: In this study, we investigated the influence of CZTL on microcirculation and its underlying mechanism. Methods: A rat model of acute microcirculatory dysfunction was established by stimuli of adrenaline and ice water. The microcirculatory damage in model rats and the efficacy of CZTL were assessed by detecting laser speckle contrast imaging, coagulation function, hemorheology, vasomotor factor and microcirculation function. The potential mechanism of CZTL action was explored by the untargeted metabolomic analysis based on ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry. Results: Laser speckle contrast imaging showed that model rats suffered low perfusion in ears, feet and tails, and CZTL treatment increased microcirculatory blood flow. Coagulation function detection results showed that CZTL diminished the reduction of thrombin time, prothrombin time, activated partial thromboplastin time and the elevated fibrinogen level caused by acute microcirculatory dysfunction. Furthermore, CZTL could recover the increased blood viscosity as well as the abnormal vasomotor and microcirculation function in rats with acute microcirculatory dysfunction. Metabolomics analysis indicated that CZTL might regulate sphingolipid metabolism and arachidonic acid metabolism to exert protective effects on microcirculation. Conclusion: These results elucidated that CZTL was highly effective against microcirculatory dysfunction and its potential mechanisms related with the modulation of sphingolipid and arachidonic acid metabolic pathways. The present study provided a new perspective on the clinical application of CZTL, and it contribute to explore novel therapeutic drug against microcirculatory dysfunction.
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Affiliation(s)
- Yuanfang Sun
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guoliang Cheng
- State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co.,Ltd, Linyi, China
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Lijing Du
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yu Gan
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bing Li
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
- State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co.,Ltd, Linyi, China
| | - Shikai Yan
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
- State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co.,Ltd, Linyi, China
| | - Mingguo Shao
- State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co.,Ltd, Linyi, China
- *Correspondence: Mingguo Shao, ; Shasha Li,
| | - Huizi Jin
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
- State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co.,Ltd, Linyi, China
| | - Shasha Li
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Mingguo Shao, ; Shasha Li,
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13
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Nikolakis D, de Voogd FAE, Pruijt MJ, Grootjans J, van de Sande MG, D’Haens GR. The Role of the Lymphatic System in the Pathogenesis and Treatment of Inflammatory Bowel Disease. Int J Mol Sci 2022; 23:ijms23031854. [PMID: 35163775 PMCID: PMC8836364 DOI: 10.3390/ijms23031854] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/26/2022] [Accepted: 02/01/2022] [Indexed: 02/04/2023] Open
Abstract
Although the number of therapeutic options for the treatment of inflammatory bowel disease (IBD) has increased in recent years, patients suffer from decreased quality of life due to non-response or loss of response to the currently available treatments. An increased understanding of the disease’s etiology could provide novel insights for treatment strategies in IBD. Lymphatic system components are generally linked to immune responses and presumably related to inflammatory diseases pathophysiology. This review aims to summarize findings on immune-mediated mechanisms in lymphoid tissues linked with IBD pathogenesis and (potential) novel treatments. Enhanced innate and adaptive immune responses were observed in mesenteric lymph nodes (MLNs) and other lymphoid structures, such as Peyer’s patches, in patients with IBD and in animal models. Furthermore, the phenomenon of lymphatic obstruction in the form of granulomas in MLNs and lymphatic vessels correlates with disease activity. There is also evidence that abnormalities in the lymphatic stromal components and lymph node microbiome are common in IBD and could be exploited therapeutically. Finally, novel agents targeting lymphocyte trafficking have been added to the treatment armamentarium in the field of IBD. Overall, gut-associated lymphoid tissue plays a key role in IBD immunopathogenesis, which could offer novel therapeutic targets.
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Affiliation(s)
- Dimitrios Nikolakis
- Department of Gastroenterology, Amsterdam Institute for Gastroenterology Endocrinology and Metabolism, Academic Medical Center, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (D.N.); (F.A.E.d.V.); (M.J.P.); (J.G.)
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands;
- Department of Experimental Immunology, Amsterdam Institute for Infection & Immunity, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Onassis Foundation, 4 Aeschinou Street, 10558 Athens, Greece
| | - Floris A. E. de Voogd
- Department of Gastroenterology, Amsterdam Institute for Gastroenterology Endocrinology and Metabolism, Academic Medical Center, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (D.N.); (F.A.E.d.V.); (M.J.P.); (J.G.)
| | - Maarten J. Pruijt
- Department of Gastroenterology, Amsterdam Institute for Gastroenterology Endocrinology and Metabolism, Academic Medical Center, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (D.N.); (F.A.E.d.V.); (M.J.P.); (J.G.)
| | - Joep Grootjans
- Department of Gastroenterology, Amsterdam Institute for Gastroenterology Endocrinology and Metabolism, Academic Medical Center, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (D.N.); (F.A.E.d.V.); (M.J.P.); (J.G.)
| | - Marleen G. van de Sande
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands;
- Department of Experimental Immunology, Amsterdam Institute for Infection & Immunity, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Geert R. D’Haens
- Department of Gastroenterology, Amsterdam Institute for Gastroenterology Endocrinology and Metabolism, Academic Medical Center, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (D.N.); (F.A.E.d.V.); (M.J.P.); (J.G.)
- Correspondence:
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14
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Wang J, Goren I, Yang B, Lin S, Li J, Elias M, Fiocchi C, Rieder F. Review article: the sphingosine 1 phosphate/sphingosine 1 phosphate receptor axis - a unique therapeutic target in inflammatory bowel disease. Aliment Pharmacol Ther 2022; 55:277-291. [PMID: 34932238 PMCID: PMC8766911 DOI: 10.1111/apt.16741] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 10/03/2021] [Accepted: 12/09/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND Ozanimod, a high selective sphingosine 1 phosphate (S1P) receptor (S1PR) 1/5 modulator was approved by the Food and Drug Administration for the treatment of adult patients with moderately to severely active ulcerative colitis. Additional S1PR modulators are being tested in clinical development programmes for both ulcerative colitis and Crohn's disease. AIM To provide an overview of advances in understanding S1PRs biology and summarise preclinical and clinical investigations of S1P receptor modulators in chronic inflammatory disease with special emphasis on inflammatory bowel diseases (IBD). METHODS We performed a narrative review using PubMed and ClinicalTrials.gov. RESULTS Through S1PRs, S1P regulates multiple cellular processes, including proliferation, migration, survival, and vascular barrier integrity. The S1PRs function of regulating lymphocyte trafficking is well known, but new functions of S1PRs expand our knowledge of S1PRs biology. Several S1PR modulators are in clinical development for both ulcerative colitis and Crohn's disease and have shown promise in phase II and III studies with ozanimod now being approved for ulcerative colitis. CONCLUSIONS S1P receptor modulators constitute a novel, promising, safe, and convenient strategy for the treatment of IBD.
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Affiliation(s)
- Jie Wang
- Henan Key Laboratory of Immunology and Targeted Drug, Xinxiang Medical University, Xinxiang 453003, Henan Province, China,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Idan Goren
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA,Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel, Affiliated with Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - Bo Yang
- Henan Key Laboratory of Immunology and Targeted Drug, Xinxiang Medical University, Xinxiang 453003, Henan Province, China
| | - Sinan Lin
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA,Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jiannan Li
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Michael Elias
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Claudio Fiocchi
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA,Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute; Cleveland Clinic Foundation, Cleveland, USA
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA,Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute; Cleveland Clinic Foundation, Cleveland, USA
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15
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Harnessing murine models of Crohn's disease ileitis to advance concepts of pathophysiology and treatment. Mucosal Immunol 2022; 15:10-26. [PMID: 34316007 DOI: 10.1038/s41385-021-00433-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 02/04/2023]
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are both characterized by chronic inflammation and severe dysfunction of the gastrointestinal tract. These two forms of inflammatory bowel disease (IBD) represent distinct clinical disorders with diverse driving mechanisms; however, this divergence is not reflected in currently approved therapeutics that commonly target general proinflammatory pathways. A compelling need therefore remains to understand factors that differentiate the topology and the distinct clinical manifestations of CD versus UC, in order to develop more effective and specialized therapies. Animal models provide valuable platforms for studying IBD heterogeneity and deciphering disease-specific mechanisms. Both the established and the newly developed ileitis mouse models are characterized by various disease initiating mechanisms and diverse phenotypic outcomes that reflect the complexity of human CD-ileitis. Microbial dysbiosis, destruction of epithelial barrier integrity, immune cell deregulation, as well as the recently described genome instability and stromal cell activation have all been proposed as the triggering factors for the development of ileitis-associated pathology. In this review, we aim to critically evaluate the mechanistic underpinnings of murine models of CD-ileitis, discuss their phenotypic similarities to human disease, and envisage their further exploitation for the development of novel targeted and personalized therapeutics.
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16
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Guzman M, Lundborg LR, Yeasmin S, Tyler CJ, Zgajnar NR, Taupin V, Dobaczewska K, Mikulski Z, Bamias G, Rivera-Nieves J. An integrin αEβ7-dependent mechanism of IgA transcytosis requires direct plasma cell contact with intestinal epithelium. Mucosal Immunol 2021; 14:1347-1357. [PMID: 34417548 PMCID: PMC8528714 DOI: 10.1038/s41385-021-00439-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/09/2021] [Accepted: 07/31/2021] [Indexed: 02/04/2023]
Abstract
Efficient IgA transcytosis is critical for the maintenance of a homeostatic microbiota. In the canonical model, locally-secreted dimeric (d)IgA reaches the polymeric immunoglobulin receptor (pIgR) on intestinal epithelium via simple diffusion. A role for integrin αE(CD103)β7 during transcytosis has not been described, nor its expression by intestinal B cell lineage cells. We found that αE-deficient (αE-/-) mice have a luminal IgA deficit, despite normal antibody-secreting cells (ASC) recruitment, local IgA production and increased pIgR expression. This deficit was not due to dendritic cell (DC)-derived retinoic acid (RA) nor class-switching defects, as stool from RAG-/- mice reconstituted with αE-/- B cells was also IgA deficient. Flow cytometric, ultrastructural and transcriptional profiling showed that αEβ7-expressing ASC represent an undescribed subset of terminally-differentiated intestinal plasma cells (PC) that establishes direct cell to cell contact with intestinal epithelium. We propose that IgA not only reaches pIgR through diffusion, but that αEβ7+ PC dock with E-cadherin-expressing intestinal epithelium to directly relay IgA for transcytosis into the intestinal lumen.
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Affiliation(s)
- Mauricio Guzman
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA, USA
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Luke R Lundborg
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA, USA
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Shaila Yeasmin
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA, USA
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Christopher J Tyler
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA, USA
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Nadia R Zgajnar
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA, USA
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Vanessa Taupin
- Electron Microscopy Core Facility, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
| | - Katarzyna Dobaczewska
- Microscopy and Histology Core, La Jolla Institute of Allergy and Immunology, La Jolla, CA, USA
| | - Zbigniew Mikulski
- Microscopy and Histology Core, La Jolla Institute of Allergy and Immunology, La Jolla, CA, USA
| | - Giorgos Bamias
- GI Unit, 3rd Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
| | - Jesús Rivera-Nieves
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA, USA.
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
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17
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Günther C, Rothhammer V, Karow M, Neurath M, Winner B. The Gut-Brain Axis in Inflammatory Bowel Disease-Current and Future Perspectives. Int J Mol Sci 2021; 22:ijms22168870. [PMID: 34445575 PMCID: PMC8396333 DOI: 10.3390/ijms22168870] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/11/2021] [Accepted: 08/13/2021] [Indexed: 12/13/2022] Open
Abstract
The gut–brain axis is a bidirectional communication system driven by neural, hormonal, metabolic, immunological, and microbial signals. Signaling events from the gut can modulate brain function and recent evidence suggests that the gut–brain axis may play a pivotal role in linking gastrointestinal and neurological diseases. Accordingly, accumulating evidence has suggested a link between inflammatory bowel diseases (IBDs) and neurodegenerative, as well as neuroinflammatory diseases. In this context, clinical, epidemiological and experimental data have demonstrated that IBD predisposes a person to pathologies of the central nervous system (CNS). Likewise, a number of neurological disorders are associated with changes in the intestinal environment, which are indicative for disease-mediated gut–brain inter-organ communication. Although this axis was identified more than 20 years ago, the sequence of events and underlying molecular mechanisms are poorly defined. The emergence of precision medicine has uncovered the need to take into account non-intestinal symptoms in the context of IBD that could offer the opportunity to tailor therapies to individual patients. The aim of this review is to highlight recent findings supporting the clinical and biological link between the gut and brain, as well as its clinical significance for IBD as well as neurodegeneration and neuroinflammation. Finally, we focus on novel human-specific preclinical models that will help uncover disease mechanisms to better understand and modulate the function of this complex system.
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Affiliation(s)
- Claudia Günther
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany;
- Correspondence: (C.G.); (B.W.); Tel.: +49-(0)9131-85-45240 (C.G.); +49-(0)9131-85-39301 (B.W.)
| | - Veit Rothhammer
- Department of Neurology, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany;
| | - Marisa Karow
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany;
| | - Markus Neurath
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany;
| | - Beate Winner
- Department of Stem Cell Biology, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
- Correspondence: (C.G.); (B.W.); Tel.: +49-(0)9131-85-45240 (C.G.); +49-(0)9131-85-39301 (B.W.)
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18
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Pérez-Jeldres T, Alvarez-Lobos M, Rivera-Nieves J. Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis. Drugs 2021; 81:985-1002. [PMID: 33983615 PMCID: PMC8116828 DOI: 10.1007/s40265-021-01528-8] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2021] [Indexed: 12/12/2022]
Abstract
Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.
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Affiliation(s)
- Tamara Pérez-Jeldres
- Pontificia Universidad Católica de Chile, Santiago, Chile
- Hospital San Borja-Arriarán, Santiago, Chile
| | - Manuel Alvarez-Lobos
- Pontificia Universidad Católica de Chile, Santiago, Chile
- Hospital San Borja-Arriarán, Santiago, Chile
| | - Jesús Rivera-Nieves
- San Diego VA Medical Center (SDVAMC), San Diego, CA, USA.
- Division of Gastroenterology, Department of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive Bldg. BRF-II Rm. 4A32, San Diego, CA, 92093-0063, USA.
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19
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Wiendl M, Becker E, Müller TM, Voskens CJ, Neurath MF, Zundler S. Targeting Immune Cell Trafficking - Insights From Research Models and Implications for Future IBD Therapy. Front Immunol 2021; 12:656452. [PMID: 34017333 PMCID: PMC8129496 DOI: 10.3389/fimmu.2021.656452] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 04/16/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC) are multifactorial diseases with still unknown aetiology and an increasing prevalence and incidence worldwide. Despite plentiful therapeutic options for IBDs, the lack or loss of response in certain patients demands the development of further treatments to tackle this unmet medical need. In recent years, the success of the anti-α4β7 antibody vedolizumab highlighted the potential of targeting the homing of immune cells, which is now an important pillar of IBD therapy. Due to its complexity, leukocyte trafficking and the involved molecules offer a largely untapped resource for a plethora of potential therapeutic interventions. In this review, we aim to summarise current and future directions of specifically interfering with immune cell trafficking. We will comment on concepts of homing, retention and recirculation and particularly focus on the role of tissue-derived chemokines. Moreover, we will give an overview of the mode of action of drugs currently in use or still in the pipeline, highlighting their mechanisms and potential to reduce disease burden.
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Affiliation(s)
- Maximilian Wiendl
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Emily Becker
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Tanja M. Müller
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Caroline J. Voskens
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Sebastian Zundler
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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20
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A Bioassay Using a Pentadecanal Derivative to Measure S1P Lyase Activity. Int J Mol Sci 2021; 22:ijms22031438. [PMID: 33535437 PMCID: PMC7867068 DOI: 10.3390/ijms22031438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/23/2021] [Accepted: 01/25/2021] [Indexed: 01/02/2023] Open
Abstract
Sphingosine-1-phosphate (S1P) is a unique lipid ligand binding to S1P receptors to transduce various cell survival or proliferation signals via small G proteins. S1P lyase (S1PL) is the specific enzyme that degrades S1P to phosphoethanolamine and (2E)-hexadecenal and therefore regulates S1P levels. S1PL also degrades dihydrosphingosine-1-phosphate (Sa1P), with a higher affinity to produce hexadecanal. Here, we developed a newly designed assay using a C17-Sa1P substrate that degrades into pentadecanal and phosphoethanolamine. For higher sensitivity in pentadecanal analysis, we developed a quantitative protocol as well as a 5,5-dimethyl cyclohexanedione (5,5-dimethyl CHD) derivatization method. The derivatization conditions were optimized for the reaction time, temperature, and concentrations of the 5,5-dimethyl CHD reagent, acetic acid, and ammonium acetate. The S1PL reaction in the cell lysate after spiking 20 µM of C17-Sa1P for 20 min was linear to the total protein concentrations of 50 µg. The S1PL levels (4 pmol/mg/min) were readily detected in this HPLC with fluorescence detection (λex = 366 nm, λem = 455 nm). The S1PL-catalyzed reaction was linear over 30 min and yielded a Km value of 2.68 μM for C17-Sa1P. This new method was validated to measure the S1PL activity of mouse embryonal carcinoma cell lines of the standard cell (F9-0), S1PL knockdown cells (F9-2), and S1PL-overexpressed cells (F9-4). Furthermore, we treated F9-4 cells with different S1PL inhibitors such as FTY720, 4-deoxypyridoxine (DOP), and the deletion of pyridoxal-5-phosphate (P5P), an essential cofactor for S1PL activity, and observed a significant decrease in pentadecanal relative to the untreated cells. In conclusion, we developed a highly sensitive S1PL assay using a C17-Sa1P substrate for pentadecanal quantification for application in the characterization of S1PL activity in vitro.
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21
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Controlling leukocyte trafficking in IBD. Pharmacol Res 2020; 159:105050. [PMID: 32598943 DOI: 10.1016/j.phrs.2020.105050] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel disease (IBD) is characterized by the accumulation of immune cells, myeloid cells and lymphocytes in the inflamed intestine. The presence and persistence of these cells, together with the production of pro-inflammatory mediators, perpetuate intestinal inflammation in both ulcerative colitis and Crohn's disease. Thus, blockade of leukocyte migration to the intestine is a main strategy used to control the disease and alleviate symptoms. Vedolizumab is the only anti-integrin drug approved for the treatment of IBD but several other drugs also targeting integrins, chemokines or receptors involved in leukocyte intestinal trafficking are under development and investigated for their efficacy and safety in IBD. The challenge now is to better understand the specific mechanism of action underlying each drug and to identify biomarkers that would guide drug selection in the individual patient.
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The Swing of Lipids at Peroxisomes and Endolysosomes in T Cell Activation. Int J Mol Sci 2020; 21:ijms21082859. [PMID: 32325900 PMCID: PMC7215844 DOI: 10.3390/ijms21082859] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 04/15/2020] [Accepted: 04/16/2020] [Indexed: 02/06/2023] Open
Abstract
The immune synapse (IS) is a well-known intercellular communication platform, organized at the interphase between the antigen presenting cell (APC) and the T cell. After T cell receptor (TCR) stimulation, signaling from plasma membrane proteins and lipids is amplified by molecules and downstream pathways for full synapse formation and maintenance. This secondary signaling event relies on intracellular reorganization at the IS, involving the cytoskeleton and components of the secretory/recycling machinery, such as the Golgi apparatus and the endolysosomal system (ELS). T cell activation triggers a metabolic reprogramming that involves the synthesis of lipids, which act as signaling mediators, and an increase of mitochondrial activity. Then, this mitochondrial activity results in elevated reactive oxygen species (ROS) production that may lead to cytotoxicity. The regulation of ROS levels requires the concerted action of mitochondria and peroxisomes. In this review, we analyze this reprogramming and the signaling implications of endolysosomal, mitochondrial, peroxisomal, and lipidic systems in T cell activation.
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Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1274:101-135. [PMID: 32894509 DOI: 10.1007/978-3-030-50621-6_6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Intensive research in the field of sphingolipids has revealed diverse roles in cell biological responses and human health and disease. This immense molecular family is primarily represented by the bioactive molecules ceramide, sphingosine, and sphingosine 1-phosphate (S1P). The flux of sphingolipid metabolism at both the subcellular and extracellular levels provides multiple opportunities for pharmacological intervention. The caveat is that perturbation of any single node of this highly regulated flux may have effects that propagate throughout the metabolic network in a dramatic and sometimes unexpected manner. Beginning with S1P, the receptors for which have thus far been the most clinically tractable pharmacological targets, this review will describe recent advances in therapeutic modulators targeting sphingolipids, their chaperones, transporters, and metabolic enzymes.
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