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Coulombeau R, Selck C, Giang N, Al‐Mohammad A, Ng N, Maher AK, Argüello R, Scalfari A, Varley J, Nicholas R, Dominguez‐Villar M. Sphingosine-1-Phosphate Signalling Inhibition Suppresses Th1-Like Treg Generation by Reversing Mitochondrial Uncoupling. Immunology 2025; 174:153-166. [PMID: 39444366 PMCID: PMC11652410 DOI: 10.1111/imm.13870] [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: 04/23/2024] [Revised: 10/04/2024] [Accepted: 10/09/2024] [Indexed: 10/25/2024] Open
Abstract
Inflammatory environments induce the generation of dysfunctional IFNγ+T-bet+FOXP3+ Th1-like Tregs, which show defective function and are found in autoimmune conditions including multiple sclerosis (MS). The pathways that control the generation of Th1-like Tregs are not well understood. Sphingosine-1-phosphate (S1P) signalling molecules are upregulated in Th1-like Tregs, and in vivo S1P inhibition with Fingolimod (FTY720) inhibits the expression of genes responsible for Treg plasticity in MS patients. However, the underlying mechanisms are unknown. Here we show that S1P signalling inhibition by FTY720 inhibits the generation of Th1-like Tregs and rescues their suppressive function. These effects are mediated by a decrease in mTORC1 signalling and reversal of the mitochondrial uncoupling that Tregs undergo during their reprogramming into Th1-like Tregs in vitro. Finally, these results are validated in in vivo-generated Th1-like Tregs, as Tregs from MS patients treated with FTY720 display decreased Th1-like Treg frequency, increased suppressive function and mitochondrial metabolism rebalance. These results highlight the involvement of mitochondrial uncoupling in Treg reprogramming and identify S1P signalling inhibition as a target to suppress the generation of dysfunctional Th1-like Tregs.
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Affiliation(s)
- Rachel Coulombeau
- Department of Infectious Disease, Faculty of MedicineImperial College LondonLondonUK
| | - Claudia Selck
- Department of Infectious Disease, Faculty of MedicineImperial College LondonLondonUK
| | - Nicolas Giang
- Department of Infectious Disease, Faculty of MedicineImperial College LondonLondonUK
| | | | - Natalie Ng
- Department of Infectious Disease, Faculty of MedicineImperial College LondonLondonUK
| | - Allison K. Maher
- Department of Infectious Disease, Faculty of MedicineImperial College LondonLondonUK
| | - Rafael Argüello
- Immunometabolism and TranslationAix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille‐LuminyMarseilleFrance
| | - Antonio Scalfari
- Centre of Neuroscience, Department of MedicineCharing Cross HospitalLondonUK
| | - James Varley
- Centre of NeuroscienceImperial College Healthcare NHS TrustLondonUK
| | - Richard Nicholas
- Centre of NeuroscienceImperial College Healthcare NHS TrustLondonUK
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Missailidis D, Ebrahimie E, Dehcheshmeh MM, Allan C, Sanislav O, Fisher P, Gras S, Annesley SJ. A blood-based mRNA signature distinguishes people with Long COVID from recovered individuals. Front Immunol 2024; 15:1450853. [PMID: 39691709 PMCID: PMC11649547 DOI: 10.3389/fimmu.2024.1450853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 11/13/2024] [Indexed: 12/19/2024] Open
Abstract
Introduction Long COVID is a debilitating condition that lasts for more than three months post-infection by SARS-CoV-2. On average, one in ten individuals infected with SARS CoV- 2 develops Long COVID worldwide. A knowledge gap exists in our understanding of the mechanisms, genetic risk factors, and biomarkers that could be associated with Long COVID. Methods In this pilot study we used RNA-Seq to quantify the transcriptomes of peripheral blood mononuclear cells isolated from COVID-recovered individuals, seven with and seven without Long COVID symptoms (age- and sex-matched individuals), on average 6 months after infection. Results Seventy genes were identified as significantly up- or down-regulated in Long COVID samples, and the vast majority were downregulated. The most significantly up- or downregulated genes fell into two main categories, either associated with cell survival or with inflammation. This included genes such as ICOS (FDR p = 0.024) and S1PR1 (FDR p = 0.019) that were both up-regulated, indicating that a pro-inflammatory state is sustained in Long COVID PBMCs compared with COVID recovered PBMCs. Functional enrichment analysis identified that immune-related functions were expectedly predominant among the up- or down-regulated genes. The most frequently downregulated genes in significantly altered functional categories were two leukocyte immunoglobulin like receptors LILRB1 (FDR p = 0.005) and LILRB2 (FDR p = 0.027). PCA analysis demonstrated that LILRB1 and LILRB2 expression discriminated all of the Long COVID samples from COVID recovered samples. Discussion Downregulation of these inhibitory receptors similarly indicates a sustained pro-inflammatory state in Long COVID PBMCs. LILRB1 and LILRB2 should be validated as prospective biomarkers of Long COVID in larger cohorts, over time and against clinically overlapping conditions.
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Affiliation(s)
- Daniel Missailidis
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
| | - Esmaeil Ebrahimie
- Genomics Research Platform, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia
- School of Animal and Veterinary Sciences, Faculty of Sciences, Engineering and Technology, University of Adelaide, Adelaide, SA, Australia
| | - Manijeh Mohammadi Dehcheshmeh
- Genomics Research Platform, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia
| | - Claire Allan
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
| | - Oana Sanislav
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
| | - Paul Fisher
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
| | - Stephanie Gras
- Infection & Immunity Program, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Bundoora, VIC, Australia
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Sarah J. Annesley
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia
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Gharagozlou S, Wright NM, Murguia-Favela L, Eshleman J, Midgley J, Saygili S, Mathew G, Lesmana H, Makkoukdji N, Gans M, Saba JD. Sphingosine phosphate lyase insufficiency syndrome as a primary immunodeficiency state. Adv Biol Regul 2024; 94:101058. [PMID: 39454238 DOI: 10.1016/j.jbior.2024.101058] [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: 09/27/2024] [Revised: 10/17/2024] [Accepted: 10/21/2024] [Indexed: 10/28/2024]
Abstract
Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a genetic disease associated with renal, endocrine, neurological, skin and immune defects. SPLIS is caused by inactivating mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). SPL catalyzes the irreversible degradation of the bioactive sphingolipid sphingosine-1-phosphate (S1P), a key regulator of lymphocyte egress. The SPL reaction represents the only exit point of sphingolipid metabolism, and SPL insufficiency causes widespread sphingolipid derangements that could additionally contribute to immunodeficiency. Herein, we review SPLIS, the sphingolipid metabolic pathway, and various roles sphingolipids play in immunity. We then explore SPLIS-related immunodeficiency by analyzing data available in the published literature supplemented by medical record reviews in ten SPLIS children. We found 93% of evaluable SPLIS patients had documented evidence of immunodeficiency. Many of the remainder of cases were unevaluable due to lack of available immunological data. Most commonly, SPLIS patients exhibited lymphopenia and T cell-specific lymphopenia, consistent with the established role of the S1P/S1P1/SPL axis in lymphocyte egress. However, low B and NK cell counts, hypogammaglobulinemia, and opportunistic infections with bacterial, viral and fungal pathogens were observed. Diminished responses to childhood vaccinations were less frequently observed. Screening blood tests quantifying recent thymic emigrants identified some lymphopenic SPLIS patients in the newborn period. Lymphopenia has been reported to improve after cofactor supplementation in some SPLIS patients, indicating upregulation of SPL activity. A variety of treatments including immunoglobulin replacement, prophylactic antimicrobials and special preparation of blood products prior to transfusion have been employed in SPLIS. The diverse immune consequences in SPLIS patients suggest that aberrant S1P signaling may not fully explain the extent of immunodeficiency. Further study will be required to fully elucidate the complex mechanisms underlying SPLIS immunodeficiency and determine the most effective prophylaxis against infection.
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Affiliation(s)
- Saber Gharagozlou
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
| | - NicolaA M Wright
- Department of Pediatrics, Cummings School of Medicine, University of Calgary, Alberta, Canada.
| | - Luis Murguia-Favela
- Department of Pediatrics, Cummings School of Medicine, University of Calgary, Alberta, Canada.
| | - Juliette Eshleman
- Department of Pediatrics, Cummings School of Medicine, University of Calgary, Alberta, Canada.
| | - Julian Midgley
- Department of Pediatrics, Cummings School of Medicine, University of Calgary, Alberta, Canada.
| | - Seha Saygili
- Department of Pediatric Nephrology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, Turkey.
| | - Georgie Mathew
- Division of Pediatric Nephrology, Christian Medical College, Vellore, India.
| | - Harry Lesmana
- Department of Medical Genetics and Genomics, Department of Pediatric Hematology/Oncology and BMT, Cleveland Clinic, Cleveland, OH, USA.
| | - Nadia Makkoukdji
- Department of Pediatrics, Division of Allergy & Immunology University of Miami Miller School of Medicine/Jackson Memorial Hospital, Miami, FL, USA.
| | - Melissa Gans
- Department of Pediatrics, Division of Allergy & Immunology University of Miami Miller School of Medicine/Jackson Memorial Hospital, Miami, FL, USA.
| | - Julie D Saba
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, 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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Li Y, Li G, Wang Y, Li L, Song Y, Cao F, Yang K. Discovery and biological evaluation of biaryl acetamide derivatives as selective and in vivo active sphingosine kinase-2 inhibitors. Eur J Med Chem 2024; 275:116577. [PMID: 38875809 DOI: 10.1016/j.ejmech.2024.116577] [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: 04/12/2024] [Revised: 06/04/2024] [Accepted: 06/04/2024] [Indexed: 06/16/2024]
Abstract
Sphingosine kinase 2 (SphK2) has emerged as a promising target for cancer therapy due to its critical role in tumor growth. However, the lack of potent and selective inhibitors has hindered its clinical application. Herein, we report the design and synthesis of a series of novel SphK2 inhibitors, culminating in the identification of compound 12q as a highly selective and potent inhibitor of SphK2. Molecular dynamics simulations suggest that the incorporation of larger substitution groups facilitates a more effective occupation of the binding site, thereby stabilizing the complex. Compared to the widely used inhibitor ABC294640, compound 12q exhibits superior anti-proliferative activity against various cancer cells, inducing G2 phase arrest and apoptosis in liver cancer cells HepG2. Notably, 12q inhibited migration and colony formation in HepG2 and altered intracellular sphingolipid content. Moreover, intraperitoneal administration of 12q in mice resulted in decreased levels of S1P. 12q provides a valuable tool compound for exploring the therapeutic potential of targeting SphK2 in cancer.
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Affiliation(s)
- Yanan Li
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China
| | - Gang Li
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China
| | - Yiming Wang
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China
| | - Longfei Li
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China
| | - Yali Song
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China
| | - Fei Cao
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Hebei University, Baoding, Hebei, 071002, China
| | - Kan Yang
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Hebei University, Baoding, Hebei, 071002, China.
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6
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Yoshida K, Morishima Y, Ishii Y, Mastuzaka T, Shimano H, Hizawa N. Abnormal saturated fatty acids and sphingolipids metabolism in asthma. Respir Investig 2024; 62:526-530. [PMID: 38640569 DOI: 10.1016/j.resinv.2024.04.006] [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: 02/08/2024] [Revised: 03/26/2024] [Accepted: 04/11/2024] [Indexed: 04/21/2024]
Abstract
Recent advances in fatty acid analysis have highlighted the links between lipid disruption and disease development. Lipid abnormalities are well-established risk factors for many of the most common chronic illnesses, and their involvement in asthma is also becoming clear. Here, we review research demonstrating the role of abnormal lipid metabolism in asthma, with a focus on saturated fatty acids and sphingolipids. High levels of palmitic acid, the most abundant saturated fatty acid in the human body, have been found in the airways of asthmatic patients with obesity, and were shown to worsen eosinophilic airway inflammation in asthma model mice on a high-fat diet. Aside from being a building block of longer-chain fatty acids, palmitic acid is also the starting point for de novo synthesis of ceramides, a class of sphingolipids. We outline the three main pathways for the synthesis of ceramides, which have been linked to the severity of asthma and act as precursors for the dynamic lipid mediator sphingosine 1-phosphate (S1P). S1P signaling is involved in allergen-induced eosinophilic inflammation, airway hyperresponsiveness, and immune-cell trafficking. A recent study of mice with mutations for the elongation of very long-chain fatty acid family member 6 (Elovl6), an enzyme that elongates fatty acid chains, has highlighted the potential role of palmitic acid composition, and thus lipid balance, in the pathophysiology of allergic airway inflammation. Elovl6 may be a potential therapeutic target in severe asthma.
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Affiliation(s)
- Kazufumi Yoshida
- Department of Pulmonary Medicine, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan.
| | - Yuko Morishima
- Department of Pulmonary Medicine, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Yukio Ishii
- Department of Respiratory Medicine, National Hospital Organization Ibaraki Higashi National Hospital, 825 Terunuma, Tokai-Mura, Naka-Gun, Ibaraki, 319-1113, Japan
| | - Takashi Mastuzaka
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Hitoshi Shimano
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Nobuyuki Hizawa
- Department of Pulmonary Medicine, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan
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7
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Loginova N, Aniskin D, Timashev P, Ulasov I, Kharwar RK. GBM Immunotherapy: Macrophage Impacts. Immunol Invest 2024; 53:730-751. [PMID: 38634572 DOI: 10.1080/08820139.2024.2337022] [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] [Indexed: 04/19/2024]
Abstract
BACKGROUND Glioblastoma (GBM) is an extremely aggressive form of brain tumor with low survival rates. Current treatments such as chemotherapy, radiation, and surgery are problematic due to tumor growth, invasion, and tumor microenvironment. GBM cells are resistant to these standard treatments, and the heterogeneity of the tumor makes it difficult to find a universal approach. Progression of GBM and acquisition of resistance to therapy are due to the complex interplay between tumor cells and the TME. A significant portion of the TME consists of an inflammatory infiltrate, with microglia and macrophages being the predominant cells. METHODS Analysis of the literature data over a course of 5 years suggest that the tumor-associated macrophages (TAMs) are capable of releasing cytokines and growth factors that promote tumor proliferation, survival, and metastasis while inhibiting immune cell function at the same time. RESULTS Thus, immunosuppressive state, provided with this intensively studied kind of TME cells, is supposed to promote GBM development through TAMs modulation of tumor treatment-resistance and aggressiveness. Therefore, TAMs are an attractive therapeutic target in the treatment of glioblastoma. CONCLUSION This review provides a comprehensive overview of the latest research on the nature of TAMs and the development of therapeutic strategies targeting TAMs, focusing on the variety of macrophage properties, being modulated, as well as molecular targets.
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Affiliation(s)
- Nina Loginova
- Group of Experimental Biotherapy and Diagnostics, Institute for Regenerative Medicine, World-Class Research Centre "Digital Biodesign and Personalized Healthcare", I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Denis Aniskin
- Group of Experimental Biotherapy and Diagnostics, Institute for Regenerative Medicine, World-Class Research Centre "Digital Biodesign and Personalized Healthcare", I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Peter Timashev
- World-Class Research Centre "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow, Russia
| | - Ilya Ulasov
- Group of Experimental Biotherapy and Diagnostics, Institute for Regenerative Medicine, World-Class Research Centre "Digital Biodesign and Personalized Healthcare", I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Rajesh Kumar Kharwar
- Endocrine Research Laboratory, Department of Zoology, University of Lucknow, Lucknow, India
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Kemp F, Braverman EL, Byersdorfer CA. Fatty acid oxidation in immune function. Front Immunol 2024; 15:1420336. [PMID: 39007133 PMCID: PMC11240245 DOI: 10.3389/fimmu.2024.1420336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 05/31/2024] [Indexed: 07/16/2024] Open
Abstract
Cellular metabolism is a crucial determinant of immune cell fate and function. Extensive studies have demonstrated that metabolic decisions influence immune cell activation, differentiation, and cellular capacity, in the process impacting an organism's ability to stave off infection or recover from injury. Conversely, metabolic dysregulation can contribute to the severity of multiple disease conditions including autoimmunity, alloimmunity, and cancer. Emerging data also demonstrate that metabolic cues and profiles can influence the success or failure of adoptive cellular therapies. Importantly, immunometabolism is not one size fits all; and different immune cell types, and even subdivisions within distinct cell populations utilize different metabolic pathways to optimize function. Metabolic preference can also change depending on the microenvironment in which cells are activated. For this reason, understanding the metabolic requirements of different subsets of immune cells is critical to therapeutically modulating different disease states or maximizing cellular function for downstream applications. Fatty acid oxidation (FAO), in particular, plays multiple roles in immune cells, providing both pro- and anti-inflammatory effects. Herein, we review the major metabolic pathways available to immune cells, then focus more closely on the role of FAO in different immune cell subsets. Understanding how and why FAO is utilized by different immune cells will allow for the design of optimal therapeutic interventions targeting this pathway.
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Affiliation(s)
| | | | - Craig A. Byersdorfer
- Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
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9
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Liu M, You Y, Zhu H, Chen Y, Hu Z, Duan J. N-Acetylcysteine Alleviates Impaired Muscular Function Resulting from Sphingosine Phosphate Lyase Functional Deficiency-Induced Sphingoid Base and Ceramide Accumulation in Caenorhabditis elegans. Nutrients 2024; 16:1623. [PMID: 38892556 PMCID: PMC11174433 DOI: 10.3390/nu16111623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 05/18/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
Sphingosine-1-phosphate lyase (SPL) resides at the endpoint of the sphingolipid metabolic pathway, catalyzing the irreversible breakdown of sphingosine-1-phosphate. Depletion of SPL precipitates compromised muscle morphology and function; nevertheless, the precise mechanistic underpinnings remain elusive. Here, we elucidate a model of SPL functional deficiency in Caenorhabditis elegans using spl-1 RNA interference. Within these SPL-deficient nematodes, we observed diminished motility and perturbed muscle fiber organization, correlated with the accumulation of sphingoid bases, their phosphorylated forms, and ceramides (collectively referred to as the "sphingolipid rheostat"). The disturbance in mitochondrial morphology was also notable, as SPL functional loss resulted in heightened levels of reactive oxygen species. Remarkably, the administration of the antioxidant N-acetylcysteine (NAC) ameliorates locomotor impairment and rectifies muscle fiber disarray, underscoring its therapeutic promise for ceramide-accumulation-related muscle disorders. Our findings emphasize the pivotal role of SPL in preserving muscle integrity and advocate for exploring antioxidant interventions, such as NAC supplementation, as prospective therapeutic strategies for addressing muscle function decline associated with sphingolipid/ceramide metabolism disruption.
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Affiliation(s)
| | | | | | | | - Zhenying Hu
- Jiangxi Province Key Laboratory of Aging and Disease, Human Aging Research Institute (HARI), School of Life Science, Nanchang University, Nanchang 330031, China
| | - Jingjing Duan
- Jiangxi Province Key Laboratory of Aging and Disease, Human Aging Research Institute (HARI), School of Life Science, Nanchang University, Nanchang 330031, China
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10
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Nojima H, Shimizu H, Murakami T, Shuto K, Koda K. Critical Roles of the Sphingolipid Metabolic Pathway in Liver Regeneration, Hepatocellular Carcinoma Progression and Therapy. Cancers (Basel) 2024; 16:850. [PMID: 38473211 DOI: 10.3390/cancers16050850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/14/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
The sphingolipid metabolic pathway, an important signaling pathway, plays a crucial role in various physiological processes including cell proliferation, survival, apoptosis, and immune regulation. The liver has the unique ability to regenerate using bioactive lipid mediators involving multiple sphingolipids, including ceramide and sphingosine 1-phosphate (S1P). Dysregulation of the balance between sphingomyelin, ceramide, and S1P has been implicated in the regulation of liver regeneration and diseases, including liver fibrosis and hepatocellular carcinoma (HCC). Understanding and modulating this balance may have therapeutic implications for tumor proliferation, progression, and metastasis in HCC. For cancer therapy, several inhibitors and activators of sphingolipid signaling, including ABC294640, SKI-II, and FTY720, have been discussed. Here, we elucidate the critical roles of the sphingolipid pathway in the regulation of liver regeneration, fibrosis, and HCC. Regulation of sphingolipids and their corresponding enzymes may considerably influence new insights into therapies for various liver disorders and diseases.
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Affiliation(s)
- Hiroyuki Nojima
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Hiroaki Shimizu
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Takashi Murakami
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Kiyohiko Shuto
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Keiji Koda
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
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11
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Suilik HA, Jaber F, Abuelazm M, Ramadan A, Elzeftawy MA, Elrosasy A, Youssef RA, Abdelazeem B, Hashash JG, Farraye FA, Ghoz H. Sphingosine 1-phosphate (S1P) receptor modulators as an induction and maintenance therapy for ulcerative colitis: a systematic review and meta-analysis of randomized controlled trials. Inflamm Res 2024; 73:183-198. [PMID: 38153524 DOI: 10.1007/s00011-023-01829-6] [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: 09/02/2023] [Revised: 09/02/2023] [Accepted: 11/27/2023] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND AND OBJECTIVE One sphingosine-1-phosphate (S1P) receptor modulator is approved (ozanimod) and another (etrasimod) is under investigation for the induction and maintenance of remission of ulcerative colitis (UC). We aim to evaluate the efficacy and safety of S1P modulators in patients with active UC. METHODS We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by systematically searching: PubMed, Web of Science, SCOPUS, and Cochrane through May 13th, 2023. We used the fixed-effect model to pool dichotomous data using risk ratio (RR) with a 95% confidence interval (CI). RESULTS Five RCTs with a total of 1990 patients were included. S1P receptor modulators were significantly associated with increased clinical response during both the induction (RR 1.71 with 95% CI [1.50, 1.94], P = 0.00001) and maintenance phases (RR 1.89 with 95% CI [1.33, 2.69], P = 0.0004); clinical remission rates during both induction (RR 2.76 with 95% CI [1.88, 4.05], P = 0.00001) and maintenance phases (RR 3.34 with 95% CI [1.41, 7.94], P = 0.006); endoscopic improvement during both induction (RR 2.15 with 95% CI [1.71, 2.70], P = 0.00001) and maintenance phases (RR 2.41 with 95% CI [1.15, 5.05], P = 0.02); and histologic remission during both induction (RR 2.60 with 95% CI [1.89, 3.57] [1.17, 2.10], P = 0.00001) and maintenance phases (RR 2.52 with 95% CI [1.89, 3.37], P = 0.00001). Finally, there was no difference regarding safety outcomes as compared to placebo in both the induction and maintenance phases. CONCLUSION S1P receptor modulators are effective in inducing and maintaining remission in patients with moderate to severe UC.
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Affiliation(s)
| | - Fouad Jaber
- Department of Internal Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.
| | | | - Alaa Ramadan
- Faculty of Medicine, South Valley University, Qena, Egypt
| | | | - Amr Elrosasy
- Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Basel Abdelazeem
- West Virginia University, Morgantown, WV, USA
- Michigan State University, East Lansing, MI, USA
| | - Jana G Hashash
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Francis A Farraye
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Hassan Ghoz
- Division of Gastroenterology and Hepatology, University of Missouri-Kansas City, Kansas City, MO, USA
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12
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Khan R, Oskouian B, Lee JY, Hodgin JB, Yang Y, Tassew G, Saba JD. AAV-SPL 2.0, a Modified Adeno-Associated Virus Gene Therapy Agent for the Treatment of Sphingosine Phosphate Lyase Insufficiency Syndrome. Int J Mol Sci 2023; 24:15560. [PMID: 37958544 PMCID: PMC10648410 DOI: 10.3390/ijms242115560] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/17/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is an inborn error of metabolism caused by inactivating mutations in SGPL1, the gene encoding sphingosine-1-phosphate lyase (SPL), an essential enzyme needed to degrade sphingolipids. SPLIS features include glomerulosclerosis, adrenal insufficiency, neurological defects, ichthyosis, and immune deficiency. Currently, there is no cure for SPLIS, and severely affected patients often die in the first years of life. We reported that adeno-associated virus (AAV) 9-mediated SGPL1 gene therapy (AAV-SPL) given to newborn Sgpl1 knockout mice that model SPLIS and die in the first few weeks of life prolonged their survival to 4.5 months and prevented or delayed the onset of SPLIS phenotypes. In this study, we tested the efficacy of a modified AAV-SPL, which we call AAV-SPL 2.0, in which the original cytomegalovirus (CMV) promoter driving the transgene is replaced with the synthetic "CAG" promoter used in several clinically approved gene therapy agents. AAV-SPL 2.0 infection of human embryonic kidney (HEK) cells led to 30% higher SPL expression and enzyme activity compared to AAV-SPL. Newborn Sgpl1 knockout mice receiving AAV-SPL 2.0 survived ≥ 5 months and showed normal neurodevelopment, 85% of normal weight gain over the first four months, and delayed onset of proteinuria. Over time, treated mice developed nephrosis and glomerulosclerosis, which likely resulted in their demise. Our overall findings show that AAV-SPL 2.0 performs equal to or better than AAV-SPL. However, improved kidney targeting may be necessary to achieve maximally optimized gene therapy as a potentially lifesaving SPLIS treatment.
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Affiliation(s)
- Ranjha Khan
- Department of Pediatrics, Division of Hematology/Oncology, University of California, San Francisco, CA 94143, USA
| | - Babak Oskouian
- Department of Pediatrics, Division of Hematology/Oncology, University of California, San Francisco, CA 94143, USA
| | - Joanna Y Lee
- Department of Pediatrics, Division of Hematology/Oncology, University of California, San Francisco, CA 94143, USA
| | - Jeffrey B Hodgin
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
| | - Yingbao Yang
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
| | - Gizachew Tassew
- Department of Pediatrics, Division of Hematology/Oncology, University of California, San Francisco, CA 94143, USA
| | - Julie D Saba
- Department of Pediatrics, Division of Hematology/Oncology, University of California, San Francisco, CA 94143, USA
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13
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Sharma S, Chepurna O, Sun T. Drug resistance in glioblastoma: from chemo- to immunotherapy. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:688-708. [PMID: 38239396 PMCID: PMC10792484 DOI: 10.20517/cdr.2023.82] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/07/2023] [Accepted: 09/25/2023] [Indexed: 01/22/2024]
Abstract
As the most common and aggressive type of primary brain tumor in adults, glioblastoma is estimated to end over 10,000 lives each year in the United States alone. Stand treatment for glioblastoma, including surgery followed by radiotherapy and chemotherapy (i.e., Temozolomide), has been largely unchanged since early 2000. Cancer immunotherapy has significantly shifted the paradigm of cancer management in the past decade with various degrees of success in treating many hematopoietic cancers and some solid tumors, such as melanoma and non-small cell lung cancer (NSCLC). However, little progress has been made in the field of neuro-oncology, especially in the application of immunotherapy to glioblastoma treatment. In this review, we attempted to summarize the common drug resistance mechanisms in glioblastoma from Temozolomide to immunotherapy. Our intent is not to repeat the well-known difficulty in the area of neuro-oncology, such as the blood-brain barrier, but to provide some fresh insights into the molecular mechanisms responsible for resistance by summarizing some of the most recent literature. Through this review, we also hope to share some new ideas for improving the immunotherapy outcome of glioblastoma treatment.
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Affiliation(s)
| | | | - Tao Sun
- Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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14
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Gordon H, Rodger B, Lindsay JO, Stagg AJ. Recruitment and Residence of Intestinal T Cells - Lessons for Therapy in Inflammatory Bowel Disease. J Crohns Colitis 2023; 17:1326-1341. [PMID: 36806613 DOI: 10.1093/ecco-jcc/jjad027] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Indexed: 02/23/2023]
Abstract
Targeting leukocyte trafficking in the management of inflammatory bowel disease [IBD] has been a significant therapeutic advance over the past 15 years. However, as with other advanced therapies, phase III clinical trials report response to trafficking inhibitors in only a proportion of patients, with fewer achieving clinical remission or mucosal healing. Additionally, there have been significant side effects, most notably progressive multifocal leukoencephalopathy in association with the α4 inhibitor natalizumab. This article reviews the mechanisms underpinning T cell recruitment and residence, to provide a background from which the strength and limitations of agents that disrupt leukocyte trafficking can be further explored. The therapeutic impact of trafficking inhibitors is underpinned by the complexity and plasticity of the intestinal immune response. Pathways essential for gut homing in health may be bypassed in the inflamed gut, thus providing alternative routes of entry when conventional homing molecules are targeted. Furthermore, there is conservation of trafficking architecture between proinflammatory and regulatory T cells. The persistence of resident memory cells within the gut gives rise to local established pro-inflammatory populations, uninfluenced by inhibition of trafficking. Finally, trafficking inhibitors may give rise to effects beyond the intended response, such as the impact of vedolizumab on innate immunity, as well as on target side effects. With significant research efforts into predictive biomarkers already underway, it is ultimately hoped that a better understanding of trafficking and residence will help us predict which patients are most likely to respond to inhibition of leukocyte trafficking, and how best to combine therapies.
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Affiliation(s)
- Hannah Gordon
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
- Department of Gastroenterology, Barts Health NHS Trust, London, UK
| | - Beverley Rodger
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
| | - James O Lindsay
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
- Department of Gastroenterology, Barts Health NHS Trust, London, UK
| | - Andrew J Stagg
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
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15
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Dertschnig S, Passweg J, Bucher C, Medinger M, Tzankov A. Mocravimod, a S1P receptor modulator, increases T cell counts in bone marrow biopsies from patients undergoing allogeneic hematopoietic stem cell transplantation. Cell Immunol 2023; 388-389:104719. [PMID: 37141843 DOI: 10.1016/j.cellimm.2023.104719] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/27/2023] [Accepted: 04/21/2023] [Indexed: 05/06/2023]
Abstract
Graft-versus-leukemia (GvL) effects are critical to prevent relapses after allogeneic hematopoietic cell transplantation (allo-HCT). However, the success of allo-HCT is limited by graft-versus-host disease (GvHD). Both, CD4+ and CD8+ T cells contribute to GvHD and GvL. The sphingosine-1-phosphate receptor (S1PR) signaling plays a crucial role in lymphocyte trafficking. Mocravimod is an S1PR modulator and its administration leads to blocking lymphocyte egress from lymphoid organs. We hypothesized that this applies to the bone marrow (BM) too, and analyzed BM biopsies from the clinical study with mocravimod (phase I trial in allo-HCT patients; NCT01830010) by immunohistochemical staining for CD3, CD4, CD8, TIA1, FoxP3, PD1, T-Bet, GATA3, and ROR-γt to identify and quantify T cell subsets in situ. Allo-HCT patients without receiving mocravimod were used as controls. BM from 9 patients in the mocravimod group and 10 patients in the control group were examined. CD3+ T cells were found to accumulate in the BM of mocravimod-treated patients compared to controls, both on day 30 and 90 post-transplant. The effect was stronger for CD4+ T cells, than CD8+ T cells, which is in line with data from murine studies showing that CD4+ T cells are more sensitive to mocravimod treatment than CD8+ T cells. Clinically-relevant acute GvHD events (grade II-IV) were slightly lower, but comparable to controls when mocravimod was administered. Taken together, data are supportive of mocravimod's mode of action and bring additional evidence of fewer relapses for allo-HCT patients treated with S1PR modulators.
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Affiliation(s)
| | - Jakob Passweg
- Hematology, University Hospital Basel, Basel, Switzerland
| | | | | | - Alexandar Tzankov
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
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16
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Fukuzaki Y, Faustino J, Lecuyer M, Rayasam A, Vexler ZS. Global sphingosine-1-phosphate receptor 2 deficiency attenuates neuroinflammation and ischemic-reperfusion injury after neonatal stroke. iScience 2023; 26:106340. [PMID: 37009213 PMCID: PMC10064246 DOI: 10.1016/j.isci.2023.106340] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 10/31/2022] [Accepted: 03/01/2023] [Indexed: 03/07/2023] Open
Abstract
Arterial ischemic stroke is common in neonates-1 per 2,300-5,000 births-and therapeutic targets remain insufficiently defined. Sphingosine-1-phosphate receptor 2 (S1PR2), a major regulator of the CNS and immune systems, is injurious in adult stroke. Here, we assessed whether S1PR2 contributes to stroke induced by 3 h transient middle cerebral artery occlusion (tMCAO) in S1PR2 heterozygous (HET), knockout (KO), and wild type (WT) postnatal day 9 pups. HET and WT of both sexes displayed functional deficits in Open Field test whereas injured KO at 24 h reperfusion performed similarly to naives. S1PR2 deficiency protected neurons, attenuated infiltration of inflammatory monocytes, and altered vessel-microglia interactions without reducing increased cytokine levels in injured regions at 72 h. Pharmacologic inhibition of S1PR2 after tMCAO by JTE-013 attenuated injury 72 h after tMCAO. Importantly, the lack of S1PR2 alleviated anxiety and brain atrophy during chronic injury. Altogether, we identify S1PR2 as a potential new target for mitigating neonatal stroke.
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Affiliation(s)
- Yumi Fukuzaki
- Department of Neurology, University California San Francisco, Weill Institute for Neurosciences, San Francisco, CA 94158-0663, USA
| | - Joel Faustino
- Department of Neurology, University California San Francisco, Weill Institute for Neurosciences, San Francisco, CA 94158-0663, USA
| | - Matthieu Lecuyer
- Department of Neurology, University California San Francisco, Weill Institute for Neurosciences, San Francisco, CA 94158-0663, USA
| | - Aditya Rayasam
- Department of Neurology, University California San Francisco, Weill Institute for Neurosciences, San Francisco, CA 94158-0663, USA
| | - Zinaida S. Vexler
- Department of Neurology, University California San Francisco, Weill Institute for Neurosciences, San Francisco, CA 94158-0663, USA
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17
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Abstract
Sphingosine-1-phosphate (S1P) and its receptor (S1PR) are involved in the pathogenesis of multiple immune-mediated inflammatory disorders, including inflammatory bowel disease. The use of S1PR modulators represents a new therapeutic option for ulcerative colitis patients. Etrasimod is an oral selective S1PR1, S1PR4 and S1PR5 modulator that inhibits the trafficking of lymphocytes from the lymph nodes into the blood. Recently, etrasimod has demonstrated efficacy in the phase II OASIS study and its open-label extension for the treatment of ulcerative colitis patients. This article reviews the mechanism of action of etrasimod and summarizes the available clinical efficacy and safety data regarding etrasimod, which is a promising drug in the treatment of patients with moderate to severe ulcerative colitis.
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Affiliation(s)
- Pauline Wils
- Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, University of Lille, F-59000 Lille, France.,Department of Gastroenterology, Centre Hospitalier Régional Universitaire de Lille, University of Lille, 59000, France
| | - Laurent Peyrin-Biroulet
- University of Lorraine, CHRU-Nancy, Department of Gastroenterology, F-54000 Nancy, France.,University of Lorraine, Inserm, NGERE, F-54000 Nancy, France
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18
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Zhang L, Mao J, Lian Y, Liang Q, Li W, Zhao J, Pan H, Gao Z, Fang L, Yuan W, Chu Y, Shi J. Mass cytometry analysis identifies T cell immune signature of aplastic anemia and predicts the response to cyclosporine. Ann Hematol 2023; 102:529-539. [PMID: 36680600 PMCID: PMC9862246 DOI: 10.1007/s00277-023-05097-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 01/02/2023] [Indexed: 01/22/2023]
Abstract
Aplastic anemia (AA) is an auto-activated T cell-mediated bone marrow failure. Cyclosporine is often used to treat non-severe AA, which demonstrates a more heterogeneous condition than severe AA. The response rate to cyclosporine is only around 50% in non-severe AA. To better predict response to cyclosporine and pinpoint who is the appropriate candidate for cyclosporine, we performed phenotypic and functional T cell immune signature at single cell level by mass cytometry from 30 patients with non-severe AA. Unexpectedly, non-significant differences of T cell subsets were observed between AA and healthy control or cyclosporine-responder and non-responders. Interestingly, when screening the expression of co-inhibitory molecules, T cell trafficking mediators, and cytokines, we found an increase of cytotoxic T lymphocyte antigen 4 (CTLA-4) on T cells in response to cyclosporine and a lower level of CTLA-4 on CD8+ T cells was correlated to hematologic response. Moreover, a decreased expression of sphingosine-1-phosphate receptor 1 (S1P1) on naive T cells and a lower level of interleukin-9 (IL-9) on T helpers also predicted a better response to cyclosporine, respectively. Therefore, the T cell immune signature, especially in CTAL-4, S1P1, and IL-9, has a predictive value for response to cyclosporine. Collectively, our study implies that immune signature analysis of T cell by mass cytometry is a useful tool to make a strategic decision on cyclosporine treatment of AA.
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Affiliation(s)
- Lele Zhang
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Jin Mao
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Yu Lian
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Qian Liang
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Weiwang Li
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Jingyu Zhao
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Hong Pan
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Zhen Gao
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Liwei Fang
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Weiping Yuan
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Yajing Chu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China.
| | - Jun Shi
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China.
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Wang T, Zhang H, Han Y, Zheng Q, Liu H, Han M, Li Z. Reversing T Cell Dysfunction to Boost Glioblastoma Immunotherapy by Paroxetine-Mediated GRK2 Inhibition and Blockade of Multiple Checkpoints through Biomimetic Nanoparticles. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2204961. [PMID: 36698265 PMCID: PMC10037995 DOI: 10.1002/advs.202204961] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 12/02/2022] [Indexed: 05/19/2023]
Abstract
T cell dysfunction-induced tumor immune escape is particularly severe in glioblastoma (GBM), and significantly affects the efficacy of immunotherapy. It is crucial to innovatively reverse the T cell dysfunction for improving GBM immunotherapy. Herein, T cell dysfunction is remarkably reversed and immunotherapy of GBM is boosted by repurposing the U. S. Food and Drug Administration-approved antidepressant paroxetine (PX) with biomimetic nanoparticles (CS-J@CM/6 NPs). The PX is successfully applied to abrogate T cell sequestration in the bone marrow of GBM-bearing mice and increase their infiltration in tumor. The biomimetic NPs are composed of ultrasmall Cu2- x Se NPs, JQ1, and tumor cell membrane modified with CD6, and are efficiently delivered into tumor through the specific interactions between CD6 and activated leukocyte cell adhesion molecule. They ameliorate the T cell dysfunction through the double roles of loaded JQ1, which simultaneously decreases the expression of PD-1 and TIM-3 on T cells, and the expression of PD-L1 on tumor cells. The NP also induces the immunogenic cell death of tumor cells to activate immune response. The synergistic roles of PX and biomimetic CS-J@CM/6 NPs notably enhance the survival of GBM-bearing mice. This work provides new insights into tumor immunotherapy by repurposing "old drugs" with advanced NPs.
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Affiliation(s)
- Tingting Wang
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Suzhou Medical College of Soochow UniversityCollaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Hao Zhang
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Suzhou Medical College of Soochow UniversityCollaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Yaobao Han
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Suzhou Medical College of Soochow UniversityCollaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Qing Zheng
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Suzhou Medical College of Soochow UniversityCollaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Hanghang Liu
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Suzhou Medical College of Soochow UniversityCollaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Mengxiao Han
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Suzhou Medical College of Soochow UniversityCollaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Zhen Li
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Suzhou Medical College of Soochow UniversityCollaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
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20
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Kim S, Lim S, Kim B, Ritchey J, Vij K, Prior J, Marsala L, Stoner A, Gao F, Achilefu S, Cooper ML, DiPersio JF, Choi J. S100A9 upregulated by IFNGR signaling blockade functions as a novel GVHD suppressor without compromising GVL in mice. Blood 2023; 141:945-950. [PMID: 36477272 PMCID: PMC10023737 DOI: 10.1182/blood.2021012687] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 11/03/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for both malignant and nonmalignant hematologic disorders. However, graft-versus-host disease (GVHD) and malignant relapse limit its therapeutic success. We previously demonstrated that the blockade of interferon-gamma receptor (IFNGR) signaling in donor T cells resulted in a reduction in GVHD while preserving graft-versus-leukemia (GVL) effects. However, the underlying molecular mechanisms remain inconclusive. In this study, we found that S100A9 is a novel GVHD suppressor upregulated when IFNGR is blocked in T cells. Both Ifngr1-/- and S100a9-overexpressing T cells significantly reduced GVHD without compromising GVL, altering donor T-cell trafficking to GVHD target organs in our mouse model of allo-HSCT. In addition, in vivo administration of recombinant murine S100A9 proteins prolongs the overall survival of recipient mice. Furthermore, in vivo administration of anti-human IFNGRα neutralizing antibody (αhGR-Nab) significantly upregulates the expression of S100A9 in human T cells and improved GVHD in our mouse model of xenogeneic human peripheral blood mononuclear cell transplantation. Consistent with S100a9-overexpressing T cells in our allo-HSCT model, αhGR-Nab reduced human T-cell trafficking to the GVHD target organs. Taken together, S100A9, a downstream molecule suppressed by IFNGR signaling, functions as a novel GVHD suppressor without compromising GVL.
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Affiliation(s)
- Sena Kim
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Sora Lim
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Boram Kim
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Julie Ritchey
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Kiran Vij
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Julie Prior
- Molecular Imaging Center in the Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO
| | - Lynne Marsala
- Molecular Imaging Center in the Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO
| | - Alyssa Stoner
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Feng Gao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO
| | - Samuel Achilefu
- Molecular Imaging Center in the Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO
| | - Matthew L. Cooper
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - John F. DiPersio
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Jaebok Choi
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
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21
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Itani HA, Evans LC. Editorial: Inflammation in hypertensive disorders. Front Physiol 2023; 13:1085856. [PMID: 36699690 PMCID: PMC9868152 DOI: 10.3389/fphys.2022.1085856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/16/2022] [Indexed: 01/11/2023] Open
Affiliation(s)
- Hana A. Itani
- 1Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Louise C. Evans
- Department of Surgery, University of Minnesota, Minneapolis, MN, United States,*Correspondence: Louise C. Evans,
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22
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Yoshida K, Morishima Y, Ano S, Sakurai H, Kuramoto K, Tsunoda Y, Yazaki K, Nakajima M, Sherpa MT, Matsuyama M, Kiwamoto T, Matsuno Y, Ishii Y, Hayashi A, Matsuzaka T, Shimano H, Hizawa N. ELOVL6 deficiency aggravates allergic airway inflammation through the ceramide-S1P pathway in mice. J Allergy Clin Immunol 2022; 151:1067-1080.e9. [PMID: 36592705 DOI: 10.1016/j.jaci.2022.12.808] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 11/30/2022] [Accepted: 12/06/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND Elongation of very-long-chain fatty acids protein 6 (ELOVL6), an enzyme regulating elongation of saturated and monounsaturated fatty acids with C12 to C16 to those with C18, has been recently indicated to affect various immune and inflammatory responses; however, the precise process by which ELOVL6-related lipid dysregulation affects allergic airway inflammation is unclear. OBJECTIVES This study sought to evaluate the biological roles of ELOVL6 in allergic airway responses and investigate whether regulating lipid composition in the airways could be an alternative treatment for asthma. METHODS Expressions of ELOVL6 and other isoforms were examined in the airways of patients who are severely asthmatic and in mouse models of asthma. Wild-type and ELOVL6-deficient (Elovl6-/-) mice were analyzed for ovalbumin-induced, and also for house dust mite-induced, allergic airway inflammation by cell biological and biochemical approaches. RESULTS ELOVL6 expression was downregulated in the bronchial epithelium of patients who are severely asthmatic compared with controls. In asthmatic mice, ELOVL6 deficiency led to enhanced airway inflammation in which lymphocyte egress from lymph nodes was increased, and both type 2 and non-type 2 immune responses were upregulated. Lipidomic profiling revealed that the levels of palmitic acid, ceramides, and sphingosine-1-phosphate were higher in the lungs of ovalbumin-immunized Elovl6-/- mice compared with those of wild-type mice, while the aggravated airway inflammation was ameliorated by treatment with fumonisin B1 or DL-threo-dihydrosphingosine, inhibitors of ceramide synthase and sphingosine kinase, respectively. CONCLUSIONS This study illustrates a crucial role for ELOVL6 in controlling allergic airway inflammation via regulation of fatty acid composition and ceramide-sphingosine-1-phosphate biosynthesis and indicates that ELOVL6 may be a novel therapeutic target for asthma.
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Affiliation(s)
- Kazufumi Yoshida
- Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yuko Morishima
- Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
| | - Satoshi Ano
- Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Department of Respiratory Medicine, National Hospital Organization Kasumigaura Medical Center, Tsuchiura, Ibaraki, Japan
| | - Hirofumi Sakurai
- Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kenya Kuramoto
- Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yoshiya Tsunoda
- Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kai Yazaki
- Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Masayuki Nakajima
- Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Mingma Thering Sherpa
- Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Masashi Matsuyama
- Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Takumi Kiwamoto
- Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yosuke Matsuno
- Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yukio Ishii
- Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Akio Hayashi
- Exploratory Research Laboratories, Minase Research Institute, Ono Pharmaceutical Co Ltd, Mishima, Osaka, Japan; AMED-CREST, Japan Agency for Medical Research and Development (AMED), Chiyoda, Tokyo, Japan
| | - Takashi Matsuzaka
- Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; AMED-CREST, Japan Agency for Medical Research and Development (AMED), Chiyoda, Tokyo, Japan
| | - Hitoshi Shimano
- Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; AMED-CREST, Japan Agency for Medical Research and Development (AMED), Chiyoda, Tokyo, Japan
| | - Nobuyuki Hizawa
- Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
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23
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Japanese Encephalitis Vaccine Generates Cross-Reactive Memory T Cell Responses to Zika Virus in Humans. J Trop Med 2022; 2022:8379286. [DOI: 10.1155/2022/8379286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 10/22/2022] [Accepted: 11/02/2022] [Indexed: 11/21/2022] Open
Abstract
Objective. Zika virus (ZIKV) and Japanese encephalitis virus (JEV) are mosquito-borne flaviviruses with sequence homology. ZIKV circulates in some regions where JEV also circulates, or where JE vaccination is used. Cross-immunity between flaviviruses exists, but the precise mechanisms remain unclear. We previously demonstrated that T cell immunity induced by the live-attenuated Japanese encephalitis (JE) SA14-14-2 vaccine conferred protective immunity against ZIKV infection in mice, which could even bypass antibody-dependent enhancement. However, the role of T cell immune, especially memory T cell subsets, in cross-reactive immune responses between JE vaccine and ZIKV in humans has not been reported. Methods. We examined central and effector memory CD4+ and CD8+ T cell (TCM and TEM) responses (including degranulation, cytokines, and chemokines) in the presence of JEV and ZIKV, respectively, by using qualified peripheral blood mononuclear cell samples from 18 children who had recently received a two-dose course of JE vaccine SA14-14-2 as well as seven children without JE vaccination. Results. Cross-reactive CD8+ TCM in response to ZIKV was characterized by secretion of IFN-γ, whereas CD8+ TEM did not show significant upregulation of functional factors. In the presence of ZIKV, IFN-γ and TNF-α expression was upregulated by CD4+ TEM, and the expression signature of CD4+ TCM is more cytotoxic potential. Conclusions. We profiled the cross-reactive memory T cell responses to ZIKV in JE vaccine recipients. These data will provide evidence for the mechanism of cross-reactive memory T cell immune responses between JEV and ZIKV and a more refined view of bivalent vaccine design strategy.
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24
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Pallett LJ, Maini MK. Liver-resident memory T cells: life in lockdown. Semin Immunopathol 2022; 44:813-825. [PMID: 35482059 PMCID: PMC9708784 DOI: 10.1007/s00281-022-00932-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/17/2022] [Indexed: 12/15/2022]
Abstract
A subset of memory T cells has been identified in the liver with a tissue-resident profile and the capacity for long-term 'lockdown'. Here we review how they are retained in, and adapted to, the hepatic microenvironment, including its unique anatomical features and metabolic challenges. We describe potential interactions with other local cell types and the need for a better understanding of this complex bidirectional crosstalk. Pathogen or tumour antigen-specific tissue-resident memory T cells (TRM) can provide rapid frontline immune surveillance; we review the evidence for this in hepatotropic infections of major worldwide importance like hepatitis B and malaria and in liver cancers like hepatocellular carcinoma. Conversely, TRM can be triggered by pro-inflammatory and metabolic signals to mediate bystander tissue damage, with an emerging role in a number of liver pathologies. We discuss the need for liver sampling to gain a window into these compartmentalised T cells, allowing more accurate disease monitoring and future locally targeted immunotherapies.
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Affiliation(s)
- Laura J Pallett
- Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Pears Building, Rowland Hill St, London, NW3 2PP, UK.
| | - Mala K Maini
- Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Pears Building, Rowland Hill St, London, NW3 2PP, UK.
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25
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Loss of sphingosine kinase 2 promotes the expansion of hematopoietic stem cells by improving their metabolic fitness. Blood 2022; 140:1686-1701. [PMID: 35881840 DOI: 10.1182/blood.2022016112] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 07/20/2022] [Indexed: 11/20/2022] Open
Abstract
Hematopoietic stem cells (HSCs) have reduced capacities to properly maintain and replenish the hematopoietic system during myelosuppressive injury or aging. Expanding and rejuvenating HSCs for therapeutic purposes has been a long-sought goal with limited progress. Here, we show that the enzyme Sphk2 (sphingosine kinase 2), which generates the lipid metabolite sphingosine-1-phosphate, is highly expressed in HSCs. The deletion of Sphk2 markedly promotes self-renewal and increases the regenerative potential of HSCs. More importantly, Sphk2 deletion globally preserves the young HSC gene expression pattern, improves the function, and sustains the multilineage potential of HSCs during aging. Mechanistically, Sphk2 interacts with prolyl hydroxylase 2 and the Von Hippel-Lindau protein to facilitate HIF1α ubiquitination in the nucleus independent of the Sphk2 catalytic activity. Deletion of Sphk2 increases hypoxic responses by stabilizing the HIF1α protein to upregulate PDK3, a glycolysis checkpoint protein for HSC quiescence, which subsequently enhances the function of HSCs by improving their metabolic fitness; specifically, it enhances anaerobic glycolysis but suppresses mitochondrial oxidative phosphorylation and generation of reactive oxygen species. Overall, targeting Sphk2 to enhance the metabolic fitness of HSCs is a promising strategy to expand and rejuvenate functional HSCs.
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26
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Lefferts AR, Norman E, Claypool DJ, Kantheti U, Kuhn KA. Cytokine competent gut-joint migratory T Cells contribute to inflammation in the joint. Front Immunol 2022; 13:932393. [PMID: 36159826 PMCID: PMC9489919 DOI: 10.3389/fimmu.2022.932393] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 08/16/2022] [Indexed: 02/01/2023] Open
Abstract
Although studies have identified the presence of gut-associated cells in the enthesis of joints affected by spondylarthritis (SpA), a direct link through cellular transit between the gut and joint has yet to be formally demonstrated. Using KikGR transgenic mice to label in situ and track cellular trafficking from the distal colon to the joint under inflammatory conditions of both the gut and joint, we demonstrate bona-fide gut-joint trafficking of T cells from the colon epithelium, also called intraepithelial lymphocytes (IELs), to distal sites including joint enthesis, the pathogenic site of SpA. Similar to patients with SpA, colon IELs from the TNFΔARE/+ mouse model of inflammatory bowel disease and SpA display heightened TNF production upon stimulation. Using ex vivo stimulation of photo-labeled gut-joint trafficked T cells from the popliteal lymph nodes of KikGR and KikGR TNFΔARE/+ we saw that the CD4+ photo-labeled population was highly enriched for IL-17 competence in healthy as well as arthritic mice, however in the TNFΔARE/+ mice these cells were additionally enriched for TNF. Using transfer of magnetically isolated IELs from TNF+/+ and TNFΔARE/+ donors into Rag1 -/- hosts, we confirmed that IELs can exacerbate inflammatory processes in the joint. Finally, we blocked IEL recruitment to the colon epithelium using broad spectrum antibiotics in TNFΔARE/+ mice. Antibiotic-treated mice had reduced gut-joint IEL migration, contained fewer Il-17A and TNF competent CD4+ T cells, and lessened joint pathology compared to untreated littermate controls. Together these results demonstrate that pro-inflammatory colon-derived IELs can exacerbate inflammatory responses in the joint through systemic trafficking, and that interference with this process through gut-targeted approaches has therapeutic potential in SpA.
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27
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Chen H, Wang J, Zhang C, Ding P, Tian S, Chen J, Ji G, Wu T. Sphingosine 1-phosphate receptor, a new therapeutic direction in different diseases. Biomed Pharmacother 2022; 153:113341. [PMID: 35785704 DOI: 10.1016/j.biopha.2022.113341] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/22/2022] [Accepted: 06/24/2022] [Indexed: 12/01/2022] Open
Abstract
Sphingosine 1-phosphate receptor (S1PR), as a kind of G protein-coupled receptor, has five subtypes, including S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5. Sphingosine 1-phosphate receptor (S1P) and S1PR regulate the trafficking of neutrophils and some cells, which has great effects on immune systems, lung tissue, and liver tissue. Presently, many related reports have proved that S1PR has a strong effect on the migration of lymphocytes, tumor cells, neutrophils, and many other cells via the regulation of signals, pathways, and enzymes. In this way, S1PR can regulate the relative response of the organism. Thus, S1PR has become a possible target for the treatment of autoimmune diseases, pulmonary disease, liver disease, and cancer. In this review, we mainly focus on the research of the S1PR for the new therapeutic directions of different diseases and is expected to assist support in the clinic and drug use.
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Affiliation(s)
- Hongyu Chen
- Minhang Hospital, Fudan University, Shanghai 201199, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Junmin Wang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Caiyun Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Peilun Ding
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Shuxia Tian
- Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Junming Chen
- Minhang Hospital, Fudan University, Shanghai 201199, China.
| | - Guang Ji
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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28
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Mandala A, Dobrinskikh E, Janssen RC, Fiehn O, D’Alessandro A, Friedman JE, Jonscher KR. Maternal Pyrroloquinoline Quinone Supplementation Improves Offspring Liver Bioactive Lipid Profiles throughout the Lifespan and Protects against the Development of Adult NAFLD. Int J Mol Sci 2022; 23:6043. [PMID: 35682720 PMCID: PMC9181499 DOI: 10.3390/ijms23116043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/18/2022] [Accepted: 05/22/2022] [Indexed: 02/06/2023] Open
Abstract
Maternal obesity and consumption of a high-fat diet significantly elevate risk for pediatric nonalcoholic fatty liver disease (NAFLD), affecting 10% of children in the US. Almost half of these children are diagnosed with nonalcoholic steatohepatitis (NASH), a leading etiology for liver transplant. Animal models show that signs of liver injury and perturbed lipid metabolism associated with NAFLD begin in utero; however, safe dietary therapeutics to blunt developmental programming of NAFLD are unavailable. Using a mouse model of maternal Western-style diet (WD), we previously showed that pyrroloquinoline quinone (PQQ), a potent dietary antioxidant, protected offspring of WD-fed dams from development of NAFLD and NASH. Here, we used untargeted mass spectrometry-based lipidomics to delineate lipotoxic effects of WD on offspring liver and identify lipid targets of PQQ. PQQ exposure during pregnancy altered hepatic lipid profiles of WD-exposed offspring, upregulating peroxisome proliferator-activated receptor (PPAR) α signaling and mitochondrial fatty acid oxidation to markedly attenuate triglyceride accumulation beginning in utero. Surprisingly, the abundance of very long-chain ceramides, important in promoting gut barrier and hepatic function, was significantly elevated in PQQ-treated offspring. PQQ exposure reduced the hepatic phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratio in WD-fed offspring and improved glucose tolerance. Notably, levels of protective n - 3 polyunsaturated fatty acids (PUFAs) were elevated in offspring exposed to PQQ, beginning in utero, and the increase in n - 3 PUFAs persisted into adulthood. Our findings suggest that PQQ supplementation during gestation and lactation augments pathways involved in the biosynthesis of long-chain fatty acids and plays a unique role in modifying specific bioactive lipid species critical for protection against NAFLD risk in later life.
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Affiliation(s)
- Ashok Mandala
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (J.E.F.)
| | - Evgenia Dobrinskikh
- Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - Rachel C. Janssen
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (J.E.F.)
| | - Oliver Fiehn
- Genome Center-Metabolomics, University of California Davis, Davis, CA 95616, USA;
| | - Angelo D’Alessandro
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - Jacob E. Friedman
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (J.E.F.)
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Karen R. Jonscher
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (J.E.F.)
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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29
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The Immunometabolic Atlas: A tool for design and interpretation of metabolomics studies in immunology. PLoS One 2022; 17:e0268408. [PMID: 35550647 PMCID: PMC9098072 DOI: 10.1371/journal.pone.0268408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 04/28/2022] [Indexed: 11/28/2022] Open
Abstract
Immunometabolism, which concerns the interplay between metabolism and the immune system, is increasingly recognized as a potential source of novel drug targets and biomarkers. In this context, the use of metabolomics to identify metabolic characteristics associated with specific functional immune response processes is of value. Currently, there is a lack of tools to determine known associations between metabolites and immune processes. Consequently, interpretation of metabolites in metabolomics studies in terms of their role in the immune system, or selection of the most relevant metabolite classes to include in metabolomics studies, is challenging. Here, we describe the Immunometabolic Atlas (IMA), a public web application and library of R functions to infer immune processes associated with specific metabolites and vice versa. The IMA derives metabolite-immune process associations utilizing a protein-metabolite network analysis algorithm that associates immune system-associated annotated proteins in Gene Ontology to metabolites. We evaluated IMA inferred metabolite-immune system associations using a text mining strategy, identifying substantial overlap, but also demonstrating a significant chemical space of immune system-associated metabolites that should be confirmed experimentally. Overall, the IMA facilitates the interpretation and design of immunometabolomics studies by the association of metabolites to specific immune processes.
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30
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TIR-Domain-Containing Adapter-Inducing Interferon-β (TRIF)-Dependent Antiviral Responses Protect Mice against Ross River Virus Disease. mBio 2022; 13:e0336321. [PMID: 35089088 PMCID: PMC8725586 DOI: 10.1128/mbio.03363-21] [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] [Indexed: 11/25/2022] Open
Abstract
Ross River virus (RRV) is the major mosquito-borne virus in the South Pacific region. RRV infections are characterized by arthritic symptoms, which can last from several weeks to months. Type I interferon (IFN), the primary antiviral innate immune response, is able to modulate adaptive immune responses. The relationship between the protective role of type I IFN and the induction of signaling proteins that drive RRV disease pathogenesis remains poorly understood. In the present study, the role of TIR-domain-containing adapter-inducing interferon-β (TRIF), an essential signaling adaptor protein downstream of Toll-like receptor (TLR) 3, a key single-stranded RNA (ssRNA)-sensing receptor, was investigated. We found that TRIF-/- mice were highly susceptible to RRV infection, with severe disease, high viremia, and a low type I IFN response early during disease development, which suggests the TLR3-TRIF axis may engage early in response to RRV infection. The number and the activation level of CD4+ T cells, CD8+ T cells, and NK cells were reduced in TRIF-/- mice compared to those in infected wild-type (WT) mice. In addition, the number of germinal center B cells was lower in TRIF-/- mice than WT mice following RRV infection, with lower titers of IgG antibodies detected in infected TRIF-/- mice compared to WT. Interestingly, the requirement for TRIF to promote immunoglobulin class switch recombination was at the level of the local immune microenvironment rather than B cells themselves. The slower resolution of RRV disease in TRIF-/- mice was associated with persistence of the RRV genome in muscle tissue and a continuing IFN response. IMPORTANCE RRV has been prevalent in the South Pacific region for decades and causes substantial economic and social costs. Though RRV is geographically restricted, a number of other alphaviruses have spread globally due to expansion of the mosquito vectors and increased international travel. Since over 30 species of mosquitoes have been implicated as potent vectors for RRV dissemination, RRV has the potential to further expand its distribution. In the pathogenesis of RRV disease, it is still not clear how innate immune responses synergize with adaptive immune responses. Type I IFN is crucial for bridging innate to adaptive immune responses to viral invasion. Hence, key signaling proteins in type I IFN induction pathways, which are important for type I IFN modulation, may also play critical roles in viral pathogenesis. This study provides insight into the role of TRIF in RRV disease development.
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31
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Lam AY, Ma C, Lee JK, Bredenoord AJ. Eosinophilic esophagitis: New molecules, better life? Curr Opin Pharmacol 2022; 63:102183. [PMID: 35176546 DOI: 10.1016/j.coph.2022.102183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 01/10/2022] [Accepted: 01/12/2022] [Indexed: 11/03/2022]
Abstract
Eosinophilic esophagitis (EoE) is an antigen-mediated chronic T helper type 2 (Th2)-associated inflammatory disorder that has emerged in the last three decades as an increasingly common cause of esophageal symptoms. Despite rising incidence and prevalence, there are currently no approved therapies for EoE in the United States and only one oral topical corticosteroid approved in Europe and Canada. Current management relies on labor- and endoscopy-intensive dietary elimination, proton-pump inhibitors (PPIs) with only moderate efficacy, and use of inhaled or nebulized topical corticosteroids designed for asthma and limited by accessibility. Fortunately, progress in elucidating the underlying pathophysiology of EoE has led to the development of new therapies derived from molecular targets necessary for disease pathogenesis. We summarize established and emerging medical therapies for EoE, with a focus on new treatments with specific molecular targets that are likely to change EoE management paradigms in the next decade.
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Affiliation(s)
- Angela Y Lam
- Department of Gastroenterology, Kaiser Permanente San Francisco, San Francisco, CA, USA
| | - Christopher Ma
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Jeffrey K Lee
- Department of Gastroenterology, Kaiser Permanente San Francisco, San Francisco, CA, USA; Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Albert J Bredenoord
- Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, the Netherlands.
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32
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Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate. Nat Commun 2022; 13:731. [PMID: 35136060 PMCID: PMC8826421 DOI: 10.1038/s41467-022-28417-2] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 01/21/2022] [Indexed: 12/23/2022] Open
Abstract
Lysophospholipids are bioactive lipids and can signal through G-protein-coupled receptors (GPCRs). The best studied lysophospholipids are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). The mechanisms of lysophospholipid recognition by an active GPCR, and the activations of lysophospholipid GPCR–G-protein complexes remain unclear. Here we report single-particle cryo-EM structures of human S1P receptor 1 (S1P1) and heterotrimeric Gi complexes formed with bound S1P or the multiple sclerosis (MS) treatment drug Siponimod, as well as human LPA receptor 1 (LPA1) and Gi complexes in the presence of LPA. Our structural and functional data provide insights into how LPA and S1P adopt different conformations to interact with their cognate GPCRs, the selectivity of the homologous lipid GPCRs for S1P versus LPA, and the different activation mechanisms of these GPCRs by LPA and S1P. Our studies also reveal specific optimization strategies to improve the MS-treating S1P1-targeting drugs. Liu et al. report structures of human sphingosine 1-phosphate (S1P) receptor 1 (S1P1) in complex with Gi and S1P or the multiple sclerosis (MS) drug Siponimod, as well as human lysophosphatidic acid (LPA) receptor 1 (LPA1) in complex with Gi and LPA, revealing distinct conformations of the lysophospholipids interacting with their cognate GPCRs.
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In Vitro Characterization of Sphingosine 1-Phosphate Receptor 1 (S1P 1) Expression and Mediated Migration of Primary Human T and B Cells in the Context of Cenerimod, a Novel, Selective S1P 1 Receptor Modulator. Int J Mol Sci 2022; 23:ijms23031191. [PMID: 35163112 PMCID: PMC8835580 DOI: 10.3390/ijms23031191] [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: 11/29/2021] [Revised: 01/07/2022] [Accepted: 01/18/2022] [Indexed: 01/27/2023] Open
Abstract
Cenerimod is a potent, selective sphingosine 1-phosphate receptor 1 (S1P1) modulator currently investigated in a Phase IIb study in patients with systemic lupus erythematosus (SLE) (NCT03742037). S1P1 receptor modulators sequester circulating lymphocytes within lymph nodes, thereby reducing pathogenic autoimmune cells (including T and B lymphocytes) in the bloodstream and inflamed tissues, making them an effective therapeutic concept for autoimmune disorders. Although the effect of S1P receptor modulators in reducing circulating lymphocytes is well documented, the precise molecular role of the S1P1 receptor on these cell types is not fully understood. In this study, the mode of action of cenerimod on human primary lymphocytes in different activation states was investigated focusing on their chemotactic behavior towards S1P in real-time, concomitant to S1P1 receptor expression and internalization dynamics. Here, we show that cenerimod effectively prevents T and B cell migration in a concentration-dependent manner. Interestingly, while T cell activation led to strong S1P1 re-expression and enhanced migration; in B cells, an enhanced migration capacity and S1P1 receptor surface expression was observed in an unstimulated state. Importantly, concomitant treatment with glucocorticoids (GCs), a frequently used treatment for autoimmune disorders, had no impact on the inhibitory activity of cenerimod on lymphocytes.
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McGowan EM, Lin Y, Chen S. Targeting Chronic Inflammation of the Digestive System in Cancer Prevention: Modulators of the Bioactive Sphingolipid Sphingosine-1-Phosphate Pathway. Cancers (Basel) 2022; 14:cancers14030535. [PMID: 35158806 PMCID: PMC8833440 DOI: 10.3390/cancers14030535] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/15/2022] [Accepted: 01/18/2022] [Indexed: 01/04/2023] Open
Abstract
Incidence of gastrointestinal (GI) cancers is increasing, and late-stage diagnosis makes these cancers difficult to treat. Chronic and low-grade inflammation are recognized risks for most GI cancers. The GI mucosal immune system maintains healthy homeostasis and signalling molecules made from saturated fats, bioactive sphingolipids, play essential roles in healthy GI immunity. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid, is a key mediator in a balanced GI immune response. Disruption in the S1P pathway underlies systemic chronic metabolic inflammatory disorders, including diabetes and GI cancers, providing a strong rationale for using modulators of the S1P pathway to treat pathological inflammation. Here, we discuss the effects of bioactive sphingolipids in immune homeostasis with a focus on S1P in chronic low-grade inflammation associated with increased risk of GI carcinogenesis. Contemporary information on S1P signalling involvement in cancers of the digestive system, from top to bottom, is reviewed. Further, we discuss the use of novel S1P receptor modulators currently in clinical trials and their potential as first-line drugs in the clinic for chronic inflammatory diseases. Recently, ozanimod (ZeposiaTM) and etrasimod have been approved for clinical use to treat ulcerative colitis and eosinophilic oesophagitis, respectively, which may have longer term benefits in reducing risk of GI cancers.
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Affiliation(s)
- Eileen M. McGowan
- Central Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China; (Y.L.); (S.C.)
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precise Therapy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
- School of Life Sciences, University of Technology Sydney, Broadway, Sydney, NSW 2007, Australia
- Correspondence: ; Tel.: +86-614-0581-4048
| | - Yiguang Lin
- Central Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China; (Y.L.); (S.C.)
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precise Therapy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
- School of Life Sciences, University of Technology Sydney, Broadway, Sydney, NSW 2007, Australia
| | - Size Chen
- Central Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China; (Y.L.); (S.C.)
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precise Therapy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
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Pediatric glioblastoma: mechanisms of immune evasion and potential therapeutic opportunities. Cancer Immunol Immunother 2022; 71:1813-1822. [PMID: 35020009 DOI: 10.1007/s00262-021-03131-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022]
Abstract
Pediatric glioblastoma is relatively rare compared with its adult counterpart but is associated with a similarly grim prognosis. Available data indicate that pediatric glioblastomas are molecularly distinct from adult tumors, and relatively little is known about the pediatric glioblastoma tumor microenvironment (TME). Cancer immunotherapy has emerged as a new pillar of cancer treatment and is revolutionizing the care of patients with many advanced solid tumors, including melanoma, non-small cell lung cancer, head and neck cancer, and renal cell carcinoma. Unfortunately, attempts to treat adult glioblastoma with current immunotherapies have had limited success to date. Nevertheless, the immune milieu in pediatric glioblastoma is distinct from that found in adult tumors, and evidence suggests that pediatric tumors are less immunosuppressive. As a result, immunotherapies should be specifically evaluated in the pediatric context. The purpose of this review is to explore known and emerging mechanisms of immune evasion in pediatric glioblastoma and highlight potential opportunities for implementing immunotherapy in the treatment of these devastating pediatric brain tumors.
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Johnson SC, Frattolin J, Edgar LT, Jafarnejad M, Moore Jr JE. Lymph node swelling combined with temporary effector T cell retention aids T cell response in a model of adaptive immunity. J R Soc Interface 2021; 18:20210464. [PMID: 34847790 PMCID: PMC8633806 DOI: 10.1098/rsif.2021.0464] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 11/02/2021] [Indexed: 12/19/2022] Open
Abstract
Swelling of lymph nodes (LNs) is commonly observed during the adaptive immune response, yet the impact on T cell (TC) trafficking and subsequent immune response is not well known. To better understand the effect of macro-scale alterations, we developed an agent-based model of the LN paracortex, describing the TC proliferative response to antigen-presenting dendritic cells alongside inflammation-driven and swelling-induced changes in TC recruitment and egress, while also incorporating regulation of the expression of egress-modulating TC receptor sphingosine-1-phosphate receptor-1. Analysis of the effector TC response under varying swelling conditions showed that swelling consistently aided TC activation. However, subsequent effector CD8+ TC production was reduced in scenarios where swelling occurred too early in the TC proliferative phase or when TC cognate frequency was low due to increased opportunity for TC exit. Temporarily extending retention of newly differentiated effector TCs, mediated by sphingosine-1-phosphate receptor-1 expression, mitigated any negative effects of swelling by allowing facilitation of activation to outweigh increased access to exit areas. These results suggest that targeting temporary effector TC retention and egress associated with swelling offers new ways to modulate effector TC responses in, for example, immuno-suppressed patients and to optimize of vaccine design.
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Affiliation(s)
- Sarah C. Johnson
- Department of Bioengineering, Imperial College London, London, UK
| | | | - Lowell T. Edgar
- Department of Bioengineering, Imperial College London, London, UK
| | - Mohammad Jafarnejad
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Singh K, Hotchkiss KM, Patel KK, Wilkinson DS, Mohan AA, Cook SL, Sampson JH. Enhancing T Cell Chemotaxis and Infiltration in Glioblastoma. Cancers (Basel) 2021; 13:5367. [PMID: 34771532 PMCID: PMC8582389 DOI: 10.3390/cancers13215367] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/22/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma is an immunologically 'cold' tumor, which are characterized by absent or minimal numbers of tumor-infiltrating lymphocytes (TILs). For those tumors that have been invaded by lymphocytes, they are profoundly exhausted and ineffective. While many immunotherapy approaches seek to reinvigorate immune cells at the tumor, this requires TILs to be present. Therefore, to unleash the full potential of immunotherapy in glioblastoma, the trafficking of lymphocytes to the tumor is highly desirable. However, the process of T cell recruitment into the central nervous system (CNS) is tightly regulated. Naïve T cells may undergo an initial licensing process to enter the migratory phenotype necessary to enter the CNS. T cells then must express appropriate integrins and selectin ligands to interact with transmembrane proteins at the blood-brain barrier (BBB). Finally, they must interact with antigen-presenting cells and undergo further licensing to enter the parenchyma. These T cells must then navigate the tumor microenvironment, which is rich in immunosuppressive factors. Altered tumoral metabolism also interferes with T cell motility. In this review, we will describe these processes and their mediators, along with potential therapeutic approaches to enhance trafficking. We also discuss safety considerations for such approaches as well as potential counteragents.
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Affiliation(s)
- Kirit Singh
- Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA; (K.M.H.); (K.K.P.); (D.S.W.); (A.A.M.); (S.L.C.)
| | | | | | | | | | | | - John H. Sampson
- Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA; (K.M.H.); (K.K.P.); (D.S.W.); (A.A.M.); (S.L.C.)
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Corbett B, Luz S, Sotuyo N, Pearson-Leary J, Moorthy GS, Zuppa AF, Bhatnagar S. FTY720 (Fingolimod), a modulator of sphingosine-1-phosphate receptors, increases baseline hypothalamic-pituitary adrenal axis activity and alters behaviors relevant to affect and anxiety. Physiol Behav 2021; 240:113556. [PMID: 34390688 DOI: 10.1016/j.physbeh.2021.113556] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 08/06/2021] [Accepted: 08/09/2021] [Indexed: 10/20/2022]
Abstract
FTY720 (fingolimod) is an analog of sphingosine, a ubiquitous sphingolipid. Phosphorylated FTY720 (FTY720-P) non-selectively binds to sphingosine-1-phosphate receptors (S1PRs) and regulates multiple cellular processes including cell proliferation, inflammation, and vascular remodeling. We recently demonstrated that S1PR3 expression in the medial prefrontal cortex (mPFC) of rats promotes stress resilience and that S1PR3 expression in blood may serve as a biomarker for PTSD. Here we investigate the effects of FTY720 in regulating the stress response. We found that single and repeated intraperitoneal injections of FTY720 increased baseline plasma adrenocorticotropic hormone (ACTH) and corticosterone concentrations. FTY720 reduced social anxiety- and despair-like behavior as assessed by increased social interaction time and reduced time spent immobile in the Porsolt forced swim test. In blood, FTY720 administration reduced lymphocyte and reticulocyte counts, but raised erythrocyte counts. FTY720 also reduced mRNA of angiopoietin 1, endothelin 1, plasminogen, TgfB2, Pdgfa, and Mmp2 in the medial prefrontal cortex, suggesting that FTY720 reduced vascular remodeling. The antidepressant-like and anxiolytic-like effects of FTY720 may be attributed to reduced vascular remodeling as increased stress-induced blood vessel density in the brain contributes to behavior associated with vulnerability in rats. Together, these results demonstrate that FTY720 regulates baseline HPA axis activity but reduces social anxiety and despair, providing further evidence that S1PRs are important and novel regulators of stress-related functions.
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Affiliation(s)
- Brian Corbett
- Center for Stress Neurobiology, Children's Hospital of Philadelphia, 3615 CIvic Center Blvd, ARC Suite 402, Philadelphia, Pennsylvania,19104-4399, USA
| | - Sandra Luz
- Center for Stress Neurobiology, Children's Hospital of Philadelphia, 3615 CIvic Center Blvd, ARC Suite 402, Philadelphia, Pennsylvania,19104-4399, USA
| | - Nathaniel Sotuyo
- Center for Stress Neurobiology, Children's Hospital of Philadelphia, 3615 CIvic Center Blvd, ARC Suite 402, Philadelphia, Pennsylvania,19104-4399, USA
| | - Jiah Pearson-Leary
- Center for Stress Neurobiology, Children's Hospital of Philadelphia, 3615 CIvic Center Blvd, ARC Suite 402, Philadelphia, Pennsylvania,19104-4399, USA
| | - Ganesh S Moorthy
- Center for Clinical Pharmacology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Athena F Zuppa
- Center for Clinical Pharmacology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Seema Bhatnagar
- Center for Stress Neurobiology, Children's Hospital of Philadelphia, 3615 CIvic Center Blvd, ARC Suite 402, Philadelphia, Pennsylvania,19104-4399, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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Abstract
PURPOSE OF REVIEW This study reviews the mechanisms of HDL cholesterol immunomodulation in the context of the mechanisms of chronic inflammation and immunosuppression causing persistent inflammation, immunosuppression and catabolism syndrome (PICS) and describes potential therapies and gaps in current research. RECENT FINDINGS Low HDL cholesterol is predictive of acute sepsis severity and outcome. Recent research has indicated apolipoprotein is a prognostic indicator of long-term outcomes. The pathobiologic mechanisms of PICS have been elucidated in the past several years. Recent research of the interaction of HDL pathways in related chronic inflammatory diseases may provide insights into further mechanisms and therapeutic targets. SUMMARY HDL significantly influences innate and adaptive immune pathways relating to chronic disease and inflammation. Further research is needed to better characterize these interactions in the setting of PICS.
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Affiliation(s)
- Grant Barker
- Department of Emergency Medicine, University of Florida College of Medicine, Jacksonville
| | - Julia R Winer
- University of Florida College of Medicine, Gainesville, Florida
| | - Faheem W Guirgis
- Department of Emergency Medicine, University of Florida College of Medicine, Jacksonville
| | - Srinivasa Reddy
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California, USA
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Saba JD, Keller N, Wang JY, Tang F, Slavin A, Shen Y. Genotype/Phenotype Interactions and First Steps Toward Targeted Therapy for Sphingosine Phosphate Lyase Insufficiency Syndrome. Cell Biochem Biophys 2021; 79:547-559. [PMID: 34133011 DOI: 10.1007/s12013-021-01013-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2021] [Indexed: 10/21/2022]
Abstract
Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder caused by a deficiency in sphingosine-1-phosphate lyase (SPL), the final enzyme in the sphingolipid degradative pathway. Inactivating mutations of SGPL1-the gene encoding SPL-lead to a deficiency of its downstream products, and buildup of sphingolipid intermediates, including its bioactive substrate, sphingosine-1-phosphate (S1P), the latter causing lymphopenia, a hallmark of the disease. Other manifestations of SPLIS include nephrotic syndrome, neuronal defects, and adrenal insufficiency, but their pathogenesis remains unknown. In this report, we describe the correlation between SGPL1 genotypes, age at diagnosis, and patient outcome. Vitamin B6 serves as a cofactor for SPL. B6 supplementation may aid some SPLIS patients by overcoming poor binding kinetics and promoting proper folding and stability of mutant SPL proteins. However, this approach remains limited to patients with a susceptible allele. Gene therapy represents a potential targeted therapy for SPLIS patients harboring B6-unresponsive missense mutations, truncations, deletions, and splice-site mutations. When Sgpl1 knockout (SPLKO) mice that model SPLIS were treated with adeno-associated virus (AAV)-mediated SGPL1 gene therapy, they showed profound improvement in survival and kidney and neurological function compared to untreated SPLKO mice. Thus, gene therapy appears promising as a universal, potentially curative treatment for SPLIS.
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Affiliation(s)
- Julie D Saba
- UCSF Department of Pediatrics, San Francisco, CA, USA.
| | - Nancy Keller
- UCSF Department of Pediatrics, San Francisco, CA, USA
| | - Jen-Yeu Wang
- UCSF Department of Pediatrics, San Francisco, CA, USA
| | - Felicia Tang
- UCSF Department of Pediatrics, San Francisco, CA, USA
| | - Avi Slavin
- UCSF Department of Pediatrics, San Francisco, CA, USA
| | - Yizhuo Shen
- UCSF Department of Pediatrics, San Francisco, CA, USA
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Jurgens AP, Popović B, Wolkers MC. T cells at work: How post-transcriptional mechanisms control T cell homeostasis and activation. Eur J Immunol 2021; 51:2178-2187. [PMID: 34180545 PMCID: PMC8457102 DOI: 10.1002/eji.202049055] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/07/2021] [Indexed: 12/19/2022]
Abstract
T cells are central players of the adaptive immune system by protecting us from recurring infections and by killing malignant cells. Protective T cell responses rely on the concerted production of effector molecules such as cytolytic mediators, granzymes, and perforins, as well as pro-inflammatory cytokines and chemokines. Once activated, T cells drastically change their gene expression and rapidly respond to insults by producing ample amounts of effector molecules. In the absence of antigen, T cells remain in a quiescent state and survey our body for possible pathogenic insults. Resting T cells are, however, not inert, but continuously regulate their protein production to survive and to be prepared for possible re-infections. Here, we review our current knowledge on the regulation of gene expression in activated and quiescent T cells. We specifically focus on post-transcriptional mechanisms that define the protein output and that allow dormant cells to undergo active signaling and selective translation, keeping them poised for activation. Finally, we discuss which signals drive T cell survival and their preparedness to respond to insults and which mechanisms are involved in these processes.
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Affiliation(s)
- Anouk P. Jurgens
- Department of HematopoiesisSanquin ResearchLandsteiner LaboratoryAmsterdam UMCUniversity of AmsterdamOncode InstituteUtrechtThe Netherlands
- Oncode InstituteUtrechtThe Netherlands
| | - Branka Popović
- Department of HematopoiesisSanquin ResearchLandsteiner LaboratoryAmsterdam UMCUniversity of AmsterdamOncode InstituteUtrechtThe Netherlands
- Oncode InstituteUtrechtThe Netherlands
| | - Monika C. Wolkers
- Department of HematopoiesisSanquin ResearchLandsteiner LaboratoryAmsterdam UMCUniversity of AmsterdamOncode InstituteUtrechtThe Netherlands
- Oncode InstituteUtrechtThe Netherlands
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Rayasam A, Fukuzaki Y, Vexler ZS. Microglia-leucocyte axis in cerebral ischaemia and inflammation in the developing brain. Acta Physiol (Oxf) 2021; 233:e13674. [PMID: 33991400 DOI: 10.1111/apha.13674] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 05/06/2021] [Accepted: 05/08/2021] [Indexed: 12/13/2022]
Abstract
Development of the Central Nervous System (CNS) is reliant on the proper function of numerous intricately orchestrated mechanisms that mature independently, including constant communication between the CNS and the peripheral immune system. This review summarizes experimental knowledge of how cerebral ischaemia in infants and children alters physiological communication between leucocytes, brain immune cells, microglia and the neurovascular unit (NVU)-the "microglia-leucocyte axis"-and contributes to acute and long-term brain injury. We outline physiological development of CNS barriers in relation to microglial and leucocyte maturation and the plethora of mechanisms by which microglia and peripheral leucocytes communicate during postnatal period, including receptor-mediated and intracellular inflammatory signalling, lipids, soluble factors and extracellular vesicles. We focus on the "microglia-leucocyte axis" in rodent models of most common ischaemic brain diseases in the at-term infants, hypoxic-ischaemic encephalopathy (HIE) and focal arterial stroke and discuss commonalities and distinctions of immune-neurovascular mechanisms in neonatal and childhood stroke compared to stroke in adults. Given that hypoxic and ischaemic brain damage involve Toll-like receptor (TLR) activation, we discuss the modulatory role of viral and bacterial TLR2/3/4-mediated infection in HIE, perinatal and childhood stroke. Furthermore, we provide perspective of the dynamics and contribution of the axis in cerebral ischaemia depending on the CNS maturational stage at the time of insult, and modulation independently and in consort by individual axis components and in a sex dependent ways. Improved understanding on how to modify crosstalk between microglia and leucocytes will aid in developing age-appropriate therapies for infants and children who suffered cerebral ischaemia.
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Affiliation(s)
- Aditya Rayasam
- Department of Neurology University of California San Francisco San Francisco CA USA
| | - Yumi Fukuzaki
- Department of Neurology University of California San Francisco San Francisco CA USA
| | - Zinaida S. Vexler
- Department of Neurology University of California San Francisco San Francisco CA USA
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Ban Y, Markowitz GJ, Zou Y, Ramchandani D, Kraynak J, Sheng J, Lee SB, Wong STC, Altorki NK, Gao D, Mittal V. Radiation-activated secretory proteins of Scgb1a1+ club cells increase the efficacy of immune checkpoint blockade in lung cancer. NATURE CANCER 2021; 2:919-931. [PMID: 34917944 PMCID: PMC8670735 DOI: 10.1038/s43018-021-00245-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 07/12/2021] [Indexed: 01/08/2023]
Abstract
Radiation therapy (RT) in combination with immune checkpoint inhibitor (ICI) represents a promising regimen for non-small cell lung cancer (NSCLC), however, the underlying mechanisms are poorly characterized. We identified a specific dose of RT that conferred tumor regression and improved survival in NSCLC models when combined with ICI. The immune-modulating functions of RT was ascribed to activated lung-resident Scgb1a1+ club cells. Importantly, mice with club cell-specific knockout of synaptosome-associated protein 23 failed to benefit from the combination treatment, indicating a pivotal role of club cell secretome. We identified 8 club cells secretory proteins, which inhibited immunosuppressive myeloid cells, reduced pro-tumor inflammation, and enhanced anti-tumor immunity. Notably, CC10, a member of club cell secretome was increased in plasma of NSCLC patients responding to the combination therapy. By revealing an immune-regulatory role of club cells, our studies have the potential to guide future clinical trials of ICI in NSCLC.
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Affiliation(s)
- Yi Ban
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA
- Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Geoffrey J Markowitz
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA
- Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Yue Zou
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA
- Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Divya Ramchandani
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA
- Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Jeffrey Kraynak
- Department of Radiology, Weill Cornell Medicine, New York, NY, USA
| | - Jianting Sheng
- Systems Medicine and Bioengineering Department and Bioinformatics and Biostatistics Cores, Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, TX, USA
| | - Sharrell B Lee
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA
- Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Stephen T C Wong
- Systems Medicine and Bioengineering Department and Bioinformatics and Biostatistics Cores, Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, TX, USA
| | - Nasser K Altorki
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA.
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA.
- Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
| | - Dingcheng Gao
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA.
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA.
- Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
| | - Vivek Mittal
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA.
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA.
- Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
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Muralidharan S, Shimobayashi M, Ji S, Burla B, Hall MN, Wenk MR, Torta F. A reference map of sphingolipids in murine tissues. Cell Rep 2021; 35:109250. [PMID: 34133933 DOI: 10.1016/j.celrep.2021.109250] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 04/21/2021] [Accepted: 05/24/2021] [Indexed: 12/12/2022] Open
Abstract
Sphingolipids (SPs) have both a structural role in the cell membranes and a signaling function that regulates many cellular processes. The enormous structural diversity and low abundance of many SPs pose a challenge for their identification and quantification. Recent advances in lipidomics, in particular liquid chromatography (LC) coupled with mass spectrometry (MS), provide methods to detect and quantify many low-abundant SP species reliably. Here we use LC-MS to compile a "murine sphingolipid atlas," containing the qualitative and quantitative distribution of 114 SPs in 21 tissues of a widely utilized wild-type laboratory mouse strain (C57BL/6). We report tissue-specific SP fingerprints, as well as sex-specific differences in the same tissue. This is a comprehensive, quantitative sphingolipidomic map of mammalian tissues collected in a systematic fashion. It will complement other tissue compendia for interrogation into the role of SP in mammalian health and disease.
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Affiliation(s)
- Sneha Muralidharan
- Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558, Singapore; Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore
| | - Mitsugu Shimobayashi
- Biozentrum - Center for Molecular Life Sciences, University of Basel, 4056 Basel, Switzerland
| | - Shanshan Ji
- Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore
| | - Bo Burla
- Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore
| | - Michael N Hall
- Biozentrum - Center for Molecular Life Sciences, University of Basel, 4056 Basel, Switzerland
| | - Markus R Wenk
- Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore.
| | - Federico Torta
- Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore.
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Trakaki A, Marsche G. Current Understanding of the Immunomodulatory Activities of High-Density Lipoproteins. Biomedicines 2021; 9:biomedicines9060587. [PMID: 34064071 PMCID: PMC8224331 DOI: 10.3390/biomedicines9060587] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 02/06/2023] Open
Abstract
Lipoproteins interact with immune cells, macrophages and endothelial cells - key players of the innate and adaptive immune system. High-density lipoprotein (HDL) particles seem to have evolved as part of the innate immune system since certain HDL subspecies contain combinations of apolipoproteins with immune regulatory functions. HDL is enriched in anti-inflammatory lipids, such as sphingosine-1-phosphate and certain saturated lysophospholipids. HDL reduces inflammation and protects against infection by modulating immune cell function, vasodilation and endothelial barrier function. HDL suppresses immune cell activation at least in part by modulating the cholesterol content in cholesterol/sphingolipid-rich membrane domains (lipid rafts), which play a critical role in the compartmentalization of signaling pathways. Acute infections, inflammation or autoimmune diseases lower HDL cholesterol levels and significantly alter HDL metabolism, composition and function. Such alterations could have a major impact on disease progression and may affect the risk for infections and cardiovascular disease. This review article aims to provide a comprehensive overview of the immune cell modulatory activities of HDL. We focus on newly discovered activities of HDL-associated apolipoproteins, enzymes, lipids, and HDL mimetic peptides.
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Zhao P, Tassew GB, Lee JY, Oskouian B, Muñoz DP, Hodgin JB, Watson GL, Tang F, Wang JY, Luo J, Yang Y, King S, Krauss RM, Keller N, Saba JD. Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome. JCI Insight 2021; 6:145936. [PMID: 33755599 PMCID: PMC8119223 DOI: 10.1172/jci.insight.145936] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 03/17/2021] [Indexed: 12/26/2022] Open
Abstract
Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder caused by inactivating mutations in sphingosine-1-phosphate lyase 1 (SGPL1), which is required for the final step of sphingolipid metabolism. SPLIS features include steroid-resistant nephrotic syndrome and impairment of neurological, endocrine, and hematopoietic systems. Many affected individuals die within the first 2 years. No targeted therapy for SPLIS is available. We hypothesized that SGPL1 gene replacement would address the root cause of SPLIS, thereby serving as a universal treatment for the condition. As proof of concept, we evaluated the efficacy of adeno-associated virus 9–mediated transfer of human SGPL1 (AAV-SPL) given to newborn Sgpl1-KO mice that model SPLIS and die in the first weeks of life. Treatment dramatically prolonged survival and prevented nephrosis, neurodevelopmental delay, anemia, and hypercholesterolemia. STAT3 pathway activation and elevated proinflammatory and profibrogenic cytokines observed in KO kidneys were attenuated by treatment. Plasma and tissue sphingolipids were reduced in treated compared with untreated KO pups. SGPL1 expression and activity were measurable for at least 40 weeks. In summary, early AAV-SPL treatment prevents nephrosis, lipidosis, and neurological impairment in a mouse model of SPLIS. Our results suggest that SGPL1 gene replacement holds promise as a durable and universal targeted treatment for SPLIS.
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Affiliation(s)
- Piming Zhao
- Department of Pediatrics, UCSF, San Francisco, California, USA.,Cure Genetics, Suzhou, China
| | | | - Joanna Y Lee
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Babak Oskouian
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Denise P Muñoz
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Jeffrey B Hodgin
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Gordon L Watson
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Felicia Tang
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Jen-Yeu Wang
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Jinghui Luo
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Yingbao Yang
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Sarah King
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Ronald M Krauss
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Nancy Keller
- Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Julie D Saba
- Department of Pediatrics, UCSF, San Francisco, California, USA
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Harlé G, Kowalski C, Dubrot J, Brighouse D, Clavel G, Pick R, Bessis N, Niven J, Scheiermann C, Gannagé M, Hugues S. Macroautophagy in lymphatic endothelial cells inhibits T cell-mediated autoimmunity. J Exp Med 2021; 218:212000. [PMID: 33861848 PMCID: PMC8056750 DOI: 10.1084/jem.20201776] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 12/21/2020] [Accepted: 02/05/2021] [Indexed: 12/11/2022] Open
Abstract
Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.
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Affiliation(s)
- Guillaume Harlé
- Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland
| | - Camille Kowalski
- Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland
| | - Juan Dubrot
- Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland
| | - Dale Brighouse
- Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland
| | - Gaëlle Clavel
- Institut National de la Santé et de la Recherche Médicale, UMR 1125, Université Sorbonne Paris Cité, Université Paris, Paris, France
| | - Robert Pick
- Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland
| | - Natacha Bessis
- Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Jennifer Niven
- Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland
| | - Christoph Scheiermann
- Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland
| | - Monique Gannagé
- Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Stéphanie Hugues
- Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland
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Monocyte-derived S1P in the lymph node regulates immune responses. Nature 2021; 592:290-295. [PMID: 33658712 PMCID: PMC8475585 DOI: 10.1038/s41586-021-03227-6] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 01/11/2021] [Indexed: 12/31/2022]
Abstract
The lipid chemoattractant sphingosine 1-phosphate (S1P) guides cells from the low-S1P environment of tissues into the high-S1P environment of circulatory fluids(1). Notably, S1P directs T cell exit from lymph nodes (LN), where T cells are initially activated, into lymph, from which T cells reach blood and ultimately inflamed tissues(1). T cells follow S1P gradients primarily using S1P receptor 1 (S1PR1)(1). While recent work has described how S1P gradients are established at steady-state, little is known about S1P distribution in disease, or about how changing S1P levels may affect immune responses. Here, we find that S1P concentrations increase in LN during an immune response. Hematopoietic cells, including inflammatory monocytes (iMo), are an important source of this S1P, an unexpected finding as endothelial cells provide lymph S1P(1). iMo require the early activation marker CD69 to supply this S1P, in part because CD69 expression is associated with reduced levels of S1pr5. CD69 acts as a “stand-your-ground” signal, keeping immune cells at a site of inflammation by regulating both S1P receptors and S1P gradients. Finally, increased S1P prolongs T cell residence time in LN, and exacerbates the severity of experimental autoimmune encephalomyelitis. This finding suggests the hypothesis that LN residence time regulates T cell differentiation, and points to novel uses of drugs targeting S1P signaling.
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Khatun A, Kasmani MY, Zander R, Schauder DM, Snook JP, Shen J, Wu X, Burns R, Chen YG, Lin CW, Williams MA, Cui W. Single-cell lineage mapping of a diverse virus-specific naive CD4 T cell repertoire. J Exp Med 2021; 218:e20200650. [PMID: 33201171 PMCID: PMC7676493 DOI: 10.1084/jem.20200650] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 08/24/2020] [Accepted: 10/22/2020] [Indexed: 12/21/2022] Open
Abstract
Tracking how individual naive T cells from a natural TCR repertoire clonally expand, differentiate, and make lineage choices in response to an infection has not previously been possible. Here, using single-cell sequencing technology to identify clones by their unique TCR sequences, we were able to trace the clonal expansion, differentiation trajectory, and lineage commitment of individual virus-specific CD4 T cells during an acute lymphocytic choriomeningitis virus (LCMV) infection. Notably, we found previously unappreciated clonal diversity and cellular heterogeneity among virus-specific helper T cells. Interestingly, although most naive CD4 T cells gave rise to multiple lineages at the clonal level, ∼28% of naive cells exhibited a preferred lineage choice toward either Th1 or TFH cells. Mechanistically, we found that TCR structure, in particular the CDR3 motif of the TCR α chain, skewed lineage decisions toward the TFH cell fate.
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Affiliation(s)
- Achia Khatun
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
| | - Moujtaba Y. Kasmani
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
| | - Ryan Zander
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
| | - David M. Schauder
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
| | - Jeremy P. Snook
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT
| | - Jian Shen
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
| | - Xiaopeng Wu
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
| | - Robert Burns
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
| | - Yi-Guang Chen
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI
- Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, Milwaukee, WI
| | - Chien-Wei Lin
- Institute for Health and Equity, Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI
| | - Matthew A. Williams
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT
| | - Weiguo Cui
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
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El Sayed R, Haibe Y, Amhaz G, Bouferraa Y, Shamseddine A. Metabolic Factors Affecting Tumor Immunogenicity: What Is Happening at the Cellular Level? Int J Mol Sci 2021; 22:2142. [PMID: 33670011 PMCID: PMC7927105 DOI: 10.3390/ijms22042142] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 02/07/2021] [Accepted: 02/11/2021] [Indexed: 12/11/2022] Open
Abstract
Immunotherapy has changed the treatment paradigm in multiple solid and hematologic malignancies. However, response remains limited in a significant number of cases, with tumors developing innate or acquired resistance to checkpoint inhibition. Certain "hot" or "immune-sensitive" tumors become "cold" or "immune-resistant", with resultant tumor growth and disease progression. Multiple factors are at play both at the cellular and host levels. The tumor microenvironment (TME) contributes the most to immune-resistance, with nutrient deficiency, hypoxia, acidity and different secreted inflammatory markers, all contributing to modulation of immune-metabolism and reprogramming of immune cells towards pro- or anti-inflammatory phenotypes. Both the tumor and surrounding immune cells require high amounts of glucose, amino acids and fatty acids to fulfill their energy demands. Thus, both compete over one pool of nutrients that falls short on needs, obliging cells to resort to alternative adaptive metabolic mechanisms that take part in shaping their inflammatory phenotypes. Aerobic or anaerobic glycolysis, oxidative phosphorylation, tryptophan catabolism, glutaminolysis, fatty acid synthesis or fatty acid oxidation, etc. are all mechanisms that contribute to immune modulation. Different pathways are triggered leading to genetic and epigenetic modulation with consequent reprogramming of immune cells such as T-cells (effector, memory or regulatory), tumor-associated macrophages (TAMs) (M1 or M2), natural killers (NK) cells (active or senescent), and dendritic cells (DC) (effector or tolerogenic), etc. Even host factors such as inflammatory conditions, obesity, caloric deficit, gender, infections, microbiota and smoking status, may be as well contributory to immune modulation, anti-tumor immunity and response to immune checkpoint inhibition. Given the complex and delicate metabolic networks within the tumor microenvironment controlling immune response, targeting key metabolic modulators may represent a valid therapeutic option to be combined with checkpoint inhibitors in an attempt to regain immune function.
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Affiliation(s)
- Rola El Sayed
- Global Health Institute, American University of Beirut, Beirut 11-0236, Lebanon;
| | - Yolla Haibe
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut 11-0236, Lebanon; (Y.H.); (G.A.); (Y.B.)
| | - Ghid Amhaz
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut 11-0236, Lebanon; (Y.H.); (G.A.); (Y.B.)
| | - Youssef Bouferraa
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut 11-0236, Lebanon; (Y.H.); (G.A.); (Y.B.)
| | - Ali Shamseddine
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut 11-0236, Lebanon; (Y.H.); (G.A.); (Y.B.)
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