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Ma Z, Hao X, Qu S, Zhang Q, Luo J, Li H, Liu J, Dai W, Li J, Gu S, Zhu D, Chen M, Zen K. Siglec-15 antibody-GM-CSF chimera suppresses tumor progression via reprogramming tumor-associated macrophages. J Immunother Cancer 2025; 13:e010580. [PMID: 40216442 PMCID: PMC11987149 DOI: 10.1136/jitc-2024-010580] [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: 09/17/2024] [Accepted: 03/26/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Sialic acid-binding immunoglobulin-like lectin (Siglec)-15-expressing tumor-associated macrophages (TAMs) drive immunosuppression in the tumor microenvironment (TME), promoting CD8+ T cell exhaustion and limiting immunotherapy efficacy. Both blockade of immune checkpoint molecule Siglec-15 and promotion of granulocyte-macrophage colony-stimulating factor (GM-CSF) have been respectively employed in anticancer immunotherapy. METHODS Murine CT26 or MC38 cancer cells were used to establish subcutaneous tumor models in BALB/c or C57BL/6 mice. Tumors were treated with anti-Siglec-15 antibody-GM-CSF chimera (anti-S15×GM CSF) or anti-Siglec-15 antibody via intraperitoneal injection. The TME was analyzed by flow cytometry and ELISA for immune cell infiltration and cytokine levels. Biodistribution and half-life of anti-S15×GM CSF were assessed by intravenous injection in tumor-bearing mice, with GM-CSF levels measured by ELISA. Macrophage reprogramming and antigen presentation were evaluated using bone marrow-derived macrophages and human peripheral blood mononuclear cell-derived macrophages treated with anti-S15×GM CSF, followed by flow cytometry and immunofluorescence assays. RESULTS Here we report that anti-S15×GM CSF displays superior function to suppress the progression of Siglec-15-overexpressing MC38 colon cancer engrafted in mice compared to anti-Siglec-15 antibody or GM-CSF alone. Different from the injected GM-CSF which is distributed broadly in various organs and tissues of mouse, the injected anti-S15×GM CSF is preferentially accumulated in Siglec-15-positive tumor cells and TAMs. Anti-S15×GM CSF not only extends the half-life of GM-CSF in vivo, but also reduces the off-target effect of GM-CSF through TAM-specific delivery. In addition to Siglec-15 blockade, anti-S15×GM CSF effectively reprograms immunosuppressive TAMs to a proinflammatory phenotype, enhancing antigen presentation by macrophages to activate T cells. CONCLUSIONS In summary, our results reveal that anti-S15×GM CSF may serve as an effective therapeutic approach for solid tumors.
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Affiliation(s)
- Zemeng Ma
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China
| | - Xiaoyao Hao
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University School of Life Sciences, Nanjing, Jiangsu 210093, China
- Biosion Inc, Nanjing, Jiangsu 210024, China
| | - Shuang Qu
- Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210024, China
| | - Quanli Zhang
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China
- Department of Scientific Research, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, 210009, China
| | - Jiajing Luo
- Medical School of Nanjing University, Nanjing, 10993, Jiangsu Province, China
| | - Hongyan Li
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University School of Life Sciences, Nanjing, Jiangsu 210093, China
- Biosion Inc, Nanjing, Jiangsu 210024, China
| | - Jinyu Liu
- Biosion Inc, Nanjing, Jiangsu 210024, China
| | - Wenwen Dai
- Biosion Inc, Nanjing, Jiangsu 210024, China
| | - Jun Li
- Biosion Inc, Nanjing, Jiangsu 210024, China
| | - Shouyong Gu
- Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210024, China
| | - Dihan Zhu
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China
| | | | - Ke Zen
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University School of Life Sciences, Nanjing, Jiangsu 210093, China
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Samuels JD, Lukens JR, Price RJ. Emerging roles for ITAM and ITIM receptor signaling in microglial biology and Alzheimer's disease-related amyloidosis. J Neurochem 2024; 168:3558-3573. [PMID: 37822118 PMCID: PMC11955997 DOI: 10.1111/jnc.15981] [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: 08/07/2023] [Revised: 09/11/2023] [Accepted: 09/21/2023] [Indexed: 10/13/2023]
Abstract
Microglia are critical responders to amyloid beta (Aβ) plaques in Alzheimer's disease (AD). Therefore, the therapeutic targeting of microglia in AD is of high clinical interest. While previous investigation has focused on the innate immune receptors governing microglial functions in response to Aβ plaques, how microglial innate immune responses are regulated is not well understood. Interestingly, many of these microglial innate immune receptors contain unique cytoplasmic motifs, termed immunoreceptor tyrosine-based activating and inhibitory motifs (ITAM/ITIM), that are commonly known to regulate immune activation and inhibition in the periphery. In this review, we summarize the diverse functions employed by microglia in response to Aβ plaques and also discuss the innate immune receptors and intracellular signaling players that guide these functions. Specifically, we focus on the role of ITAM and ITIM signaling cascades in regulating microglia innate immune responses. A better understanding of how microglial innate immune responses are regulated in AD may provide novel therapeutic avenues to tune the microglial innate immune response in AD pathology.
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Affiliation(s)
- Joshua D. Samuels
- Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia (UVA), Charlottesville, VA 22908, USA
- Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA
| | - John R. Lukens
- Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia (UVA), Charlottesville, VA 22908, USA
- Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA
| | - Richard J. Price
- Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA
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3
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McCord K, Wang C, Anhalt M, Poon WW, Gavin AL, Wu P, Macauley MS. Dissecting the Ability of Siglecs To Antagonize Fcγ Receptors. ACS CENTRAL SCIENCE 2024; 10:315-330. [PMID: 38435516 PMCID: PMC10906256 DOI: 10.1021/acscentsci.3c00969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 12/19/2023] [Accepted: 12/21/2023] [Indexed: 03/05/2024]
Abstract
Fcγ receptors (FcγRs) play key roles in the effector function of IgG, but their inappropriate activation plays a role in several disease etiologies. Therefore, it is critical to better understand how FcγRs are regulated. Numerous studies suggest that sialic acid-binding immunoglobulin-type lectins (Siglecs), a family of immunomodulatory receptors, modulate FcγR activity; however, it is unclear of the circumstances in which Siglecs can antagonize FcγRs and which Siglecs have this ability. Using liposomes displaying selective ligands to coengage FcγRs with a specific Siglec, we explore the ability of Siglec-3, Siglec-5, Siglec-7, and Siglec-9 to antagonize signaling downstream of FcγRs. We demonstrate that Siglec-3 and Siglec-9 can fully inhibit FcγR activation in U937 cells when coengaged with FcγRs. Cells expressing Siglec mutants reveal differential roles for the immunomodulatory tyrosine-based inhibitory motif (ITIM) and immunomodulatory tyrosine-based switch motif (ITSM) in this inhibition. Imaging flow cytometry enabled visualization of SHP-1 recruitment to Siglec-3 in an ITIM-dependent manner, while SHP-2 recruitment is more ITSM-dependent. Conversely, both cytosolic motifs of Siglec-9 contribute to SHP-1/2 recruitment. Siglec-7 poorly antagonizes FcγR activation for two reasons: masking by cis ligands and differences in its ITIM and ITSM. A chimera of the Siglec-3 extracellular domains and Siglec-5 cytosolic tail strongly inhibits FcγR when coengaged, providing evidence that Siglec-5 is more like Siglec-3 and Siglec-9 in its ability to antagonize FcγRs. Additionally, Siglec-3 and Siglec-9 inhibited FcγRs when coengaged by cells displaying ligands for both the Siglec and FcγRs. These results suggest a role for Siglecs in mediating FcγR inhibition in the context of an immunological synapse, which has important relevance to the effectiveness of immunotherapies.
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Affiliation(s)
- Kelli
A. McCord
- Department
of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, Alberta T6G 2G2, Canada
| | - Chao Wang
- Department
of Molecular Medicine, Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Mirjam Anhalt
- Department
of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, Alberta T6G 2G2, Canada
| | - Wayne W. Poon
- Institute
for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92617, United States
| | - Amanda L. Gavin
- Department
of Immunology and Microbiology, Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Peng Wu
- Department
of Molecular Medicine, Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Matthew S. Macauley
- Department
of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, Alberta T6G 2G2, Canada
- Department
of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
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Ogbodo AK, Mustafov D, Arora M, Lambrou GI, Braoudaki M, Siddiqui SS. Analysis of SIGLEC12 expression, immunomodulation and prognostic value in renal cancer using multiomic databases. Heliyon 2024; 10:e24286. [PMID: 38268823 PMCID: PMC10803920 DOI: 10.1016/j.heliyon.2024.e24286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 11/30/2023] [Accepted: 01/05/2024] [Indexed: 01/26/2024] Open
Abstract
Siglecs belong to a family of immune regulatory receptors predominantly found on hematopoietic cells. They interact with Sia, resulting in the activation or inhibition of the immune response. Previous reports have suggested that the SIGLEC12 gene, which encodes the Siglec-XII protein, is expressed in the epithelial tissues and upregulated in carcinomas. However, studies deciphering the role of Siglec-XII in renal cancer (RC) are still unavailable, and here we provide insights on this question. We conducted expression analysis using the Human Protein Atlas and UALCAN databases. The impact of SIGLEC12 on RC prognosis was determined using the KM plotter, and an assessment of immune infiltration with SIGLEC12 was performed using the TIMER database. GSEA was conducted to identify the pathways affected by SIGLEC12. Finally, using GeneMania, we identified Siglec-XII interacting proteins. Our findings indicated that macrophages express SIGLEC12 in the kidney. Furthermore, we hypothesize that Siglec-XII expression might be involved in the increase of primary RC, but this effect may not be dependent on the age of the patient. In the tumour microenvironment, oncogenic pathways appeared to be upregulated by SIGLEC12. Similarly, our analysis suggested that SIGLEC12-related kidney renal papillary cell carcinomas may be more suitable for targeted immunotherapy, such as CTLA-4 and PD-1/PD-L1 inhibitors. These preliminary results suggested that high expression of SIGLEC12 is associated with poor prognosis for RC. Future studies to assess its clinical utility are necessitated.
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Affiliation(s)
- Amobichukwu K. Ogbodo
- School of Life and Medical Sciences, University of Hertfordshire, College Lane Campus, Hatfield AL10 9AB, United Kingdom
- #Current Address: Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Oxford OX3 7LF, United Kingdom
| | - Denis Mustafov
- School of Life and Medical Sciences, University of Hertfordshire, College Lane Campus, Hatfield AL10 9AB, United Kingdom
- College of Health, Medicine, and Life Science, Brunel University London UB8 3PH, United Kingdom
| | - Mohit Arora
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
| | - George I. Lambrou
- Choremeio Research Laboratory, First Department of Paediatrics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece, Thivon & Levadeias 8, 11527, Goudi, Athens, Greece
- University Research Institute of Maternal and Child Health & Precision Medicine, National and Kapodistrian University of Athens, Thivon & Levadeias 8, 11527 Athens, Greece
| | - Maria Braoudaki
- School of Life and Medical Sciences, University of Hertfordshire, College Lane Campus, Hatfield AL10 9AB, United Kingdom
| | - Shoib S. Siddiqui
- School of Life and Medical Sciences, University of Hertfordshire, College Lane Campus, Hatfield AL10 9AB, United Kingdom
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Conti G, Bärenwaldt A, Rabbani S, Mühlethaler T, Sarcevic M, Jiang X, Schwardt O, Ricklin D, Pieters RJ, Läubli H, Ernst B. Tetra- and Hexavalent Siglec-8 Ligands Modulate Immune Cell Activation. Angew Chem Int Ed Engl 2023; 62:e202314280. [PMID: 37947772 DOI: 10.1002/anie.202314280] [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: 09/26/2023] [Revised: 10/31/2023] [Accepted: 11/07/2023] [Indexed: 11/12/2023]
Abstract
Carbohydrate-binding proteins are generally characterized by poor affinities for their natural glycan ligands, predominantly due to the shallow and solvent-exposed binding sites. To overcome this drawback, nature has exploited multivalency to strengthen the binding by establishing multiple interactions simultaneously. The development of oligovalent structures frequently proved to be successful, not only for proteins with multiple binding sites, but also for proteins that possess a single recognition domain. Herein we present the syntheses of a number of oligovalent ligands for Siglec-8, a monomeric I-type lectin found on eosinophils and mast cells, alongside the thermodynamic characterization of their binding. While the enthalpic contribution of each binding epitope was within a narrow range to that of the monomeric ligand, the entropy penalty increased steadily with growing valency. Additionally, we observed a successful agonistic binding of the tetra- and hexavalent and, to an even larger extent, multivalent ligands to Siglec-8 on immune cells and modulation of immune cell activation. Thus, triggering a biological effect is not restricted to multivalent ligands but could be induced by low oligovalent ligands as well, whereas a monovalent ligand, despite binding with similar affinity, showed an antagonistic effect.
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Affiliation(s)
- Gabriele Conti
- Molecular Pharmacy Group, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
- Chemical Biology and Drug Discovery Group, Department of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands
| | - Anne Bärenwaldt
- Laboratory for Cancer Immunotherapy, Department of Biomedicine, University of Basel, Hebelstrasse 20, 4051, Basel, Switzerland
- Division of Medical Oncology, University Hospital Basel, Petersgraben 4, 4051, Basel, Switzerland
| | - Said Rabbani
- Molecular Pharmacy Group, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Tobias Mühlethaler
- Biophysics Facility, Department Biozentrum, University of Basel, Spitalstrasse 41, 4056, Basel, Switzerland
| | - Mirza Sarcevic
- Laboratory for Cancer Immunotherapy, Department of Biomedicine, University of Basel, Hebelstrasse 20, 4051, Basel, Switzerland
- Division of Medical Oncology, University Hospital Basel, Petersgraben 4, 4051, Basel, Switzerland
| | - Xiaohua Jiang
- Molecular Pharmacy Group, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Oliver Schwardt
- Molecular Pharmacy Group, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Daniel Ricklin
- Molecular Pharmacy Group, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Roland J Pieters
- Chemical Biology and Drug Discovery Group, Department of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands
| | - Heinz Läubli
- Laboratory for Cancer Immunotherapy, Department of Biomedicine, University of Basel, Hebelstrasse 20, 4051, Basel, Switzerland
- Division of Medical Oncology, University Hospital Basel, Petersgraben 4, 4051, Basel, Switzerland
| | - Beat Ernst
- Molecular Pharmacy Group, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
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Sereshki N, Rafiee M, Alipour R, Rahimyan K, Wilkinson D. CD33 as a leukocyte-associated marker expressed on human spermatozoa. BMC Res Notes 2023; 16:57. [PMID: 37081561 PMCID: PMC10120122 DOI: 10.1186/s13104-023-06324-z] [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: 10/13/2022] [Accepted: 04/05/2023] [Indexed: 04/22/2023] Open
Abstract
OBJECTIVE Sialic acid-binding immunoglobulin-type lectins (Siglecs) are commonly present on immune cells and often mediate cell-to-cell interactions and signaling. Studies have shown the presence of Siglecs 1, 2, 5, 6, 10 and 14 on human spermatozoa. To the best of our knowledge, the expression of CD33 on spermatozoa has not yet been studied. Semen samples were collected from 25 healthy men with normal semen status. CD33 expression on purified spermatozoa was evaluated by flow cytometry methods. RESULTS The results demonstrate the expression of CD33 on the surface of purified spermatozoa. The mean (± SD) of MFI (mean fluorescence intensity) was 12.85 (± 1.33) and the mean percentage of spermatozoa that express CD33 was 73.75 (± 3.75). Results were obtained showing that spermatozoa express CD33 (or Siglec-3) on their surface. The physiological role of these molecules on spermatozoa remains to be determined. It is recommended that further research be undertaken regarding the role of Siglecs (such as CD33) on spermatozoa apoptosis.
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Affiliation(s)
- Nasrin Sereshki
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mitra Rafiee
- Department of Immunology, Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, 9717853577, Iran.
| | - Razieh Alipour
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Kourosh Rahimyan
- Department of Microbiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Abstract
Alzheimer's disease (AD) is a debilitating age-related neurodegenerative condition. Unbiased genetic studies have implicated a central role for microglia, the resident innate immune cells of the central nervous system, in AD pathogenesis. On-going efforts are clarifying the biology underlying these associations and the microglial pathways that are dysfunctional in AD. Several genetic risk factors converge to decrease the function of activating microglial receptors and increase the function of inhibitory receptors, resulting in a seemingly dampened microglial phenotype in AD. Moreover, many of these microglial proteins that are genetically associated with AD appear to interact and share pathways or regulatory mechanisms, presenting several points of convergence that may be strategic targets for therapeutic intervention. Here, we review some of these studies and their implications for microglial participation in AD pathogenesis.
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8
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Qazi S, Uckun FM. CD22 Exon 12 Deletion as an Independent Predictor of Poor Treatment Outcomes in B-ALL. Cancers (Basel) 2023; 15:1599. [PMID: 36900389 PMCID: PMC10000517 DOI: 10.3390/cancers15051599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 02/21/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
We previously reported a splicing defect (CD22ΔE12) associated with the deletion of exon 12 of the inhibitory co-receptor CD22 (Siglec-2) in leukemia cells from patients with CD19+ B-precursor acute lymphoblastic leukemia (B-ALL). CD22ΔE12 causes a truncating frameshift mutation and yields a dysfunctional CD22 protein that lacks most of the cytoplasmic domain required for its inhibitory function, and it is associated with aggressive in vivo growth of human B-ALL cells in mouse xenograft models. Although CD22ΔE12 with selective reduction of CD22 exon 12 (CD22E12) levels was detected in a high percentage of newly diagnosed as well as relapsed B-ALL patients, its clinical significance remains unknown. We hypothesized that B-ALL patients with very low levels of wildtype CD22 would exhibit a more aggressive disease with a worse prognosis because the missing inhibitory function of the truncated CD22 molecules could not be adequately compensated by competing wildtype CD22. Here, we demonstrate that newly diagnosed B-ALL patients with very low levels of residual wildtype CD22 ("CD22E12low"), as measured by RNAseq-based CD22E12 mRNA levels, have significantly worse leukemia-free survival (LFS) as well as overall survival (OS) than other B-ALL patients. CD22E12low status was identified as a poor prognostic indicator in both univariate and multivariate Cox proportional hazards models. CD22E12low status at presentation shows clinical potential as a poor prognostic biomarker that may guide the early allocation of risk-adjusted, patient-tailored treatment regimens and refine risk classification in high-risk B-ALL.
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Affiliation(s)
- Sanjive Qazi
- Ares Pharmaceuticals, Saint Paul, MN 55110, USA
- Division of Hematology-Oncology, Department of Pediatrics and Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA 90027, USA
| | - Fatih M. Uckun
- Ares Pharmaceuticals, Saint Paul, MN 55110, USA
- Division of Hematology-Oncology, Department of Pediatrics and Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA 90027, USA
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The Role of the JAK/STAT Signaling Pathway in the Pathogenesis of Alzheimer's Disease: New Potential Treatment Target. Int J Mol Sci 2023; 24:ijms24010864. [PMID: 36614305 PMCID: PMC9821184 DOI: 10.3390/ijms24010864] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/19/2022] [Accepted: 12/29/2022] [Indexed: 01/05/2023] Open
Abstract
Alzheimer's disease is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, emerging evidence suggests that neuroinflammation, mediated notably by activated neuroglial cells, neutrophils, and macrophages, also plays an important role in the pathogenesis of Alzheimer's disease. Therefore, understanding the interplay between the nervous and immune systems might be the key to the prevention or delay of Alzheimer's disease progression. One of the most important mechanisms determining gliogenic cell fate is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway that is influenced by the overactivation of microglia and astrocytes. The JAK/STAT signaling pathway is one of the critical factors that promote neuroinflammation in neurodegenerative diseases such as Alzheimer's disease by initiating innate immunity, orchestrating adaptive immune mechanisms, and finally, constraining neuroinflammatory response. Since a chronic neuroinflammatory environment in the brain is a hallmark of Alzheimer's disease, understanding the process would allow establishing the underlying role of neuroinflammation, then estimating the prognosis of Alzheimer's disease development and finding a new potential treatment target. In this review, we highlight the recent advances in the potential role of JAK/STAT signaling in neurological diseases with a focus on discussing future research directions regarding novel therapeutic approaches and predictive biomarkers for Alzheimer's disease.
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Huang R, Zheng J, Shao Y, Zhu L, Yang T. Siglec-15 as multifunctional molecule involved in osteoclast differentiation, cancer immunity and microbial infection. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 177:34-41. [PMID: 36265694 DOI: 10.1016/j.pbiomolbio.2022.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 09/19/2022] [Accepted: 10/13/2022] [Indexed: 11/06/2022]
Abstract
Siglec-15 is a highly conserved member of the Siglec family, expressed on osteoclasts, a subset of myeloid cells and some cancer cells. Except for regulating osteoclast differentiation, Siglec-15 engages in immunoregulation as an immune suppressor. Siglec-15 functions as an immunosuppressive molecule in tumor-associated macrophage-mediated T cell immunity in the tumor microenvironment (TME), which makes Siglec-15 to be an emerging and promising target for normalization cancer immunotherapy. Besides, Siglec-15 interacts with sialylated pathogens and modulates host immune response against microbial pathogens by altering cytokine production and/or phagocytosis, which further broadens the underlying pathophysiological roles of Siglec-15. The fact that N-glycosylation and sialylation of Siglec-15 play a pivotal role in Siglec-15 biological function indicates that targeting certain post-translational modification may be an effective strategy for targeting Siglec-15 therapy. In-depth exploring Siglec-15 biology function is crucial for better design of Siglec-15-based therapy according to different clinical indications.
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Affiliation(s)
- Rui Huang
- Department of Biochemistry & Molecular Biology, Shanxi Medical University, Taiyuan, China; Department of Clinical Laboratory, Children's Hospital and Women Health Center of Shanxi, Taiyuan, China
| | - Jinxiu Zheng
- Department of Biochemistry & Molecular Biology, Shanxi Medical University, Taiyuan, China; Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, China
| | - Ying Shao
- Department of Pathophysiology, Shanxi Medical University, Taiyuan, China
| | - Lei Zhu
- Department of Clinical Laboratory, Children's Hospital and Women Health Center of Shanxi, Taiyuan, China
| | - Tao Yang
- Department of Biochemistry & Molecular Biology, Shanxi Medical University, Taiyuan, China; Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, China.
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Boada P, Fatou B, Belperron AA, Sigdel TK, Smolen KK, Wurie Z, Levy O, Ronca SE, Murray KO, Liberto JM, Rashmi P, Kerwin M, Montgomery RR, Bockenstedt LK, Steen H, Sarwal MM. Longitudinal serum proteomics analyses identify unique and overlapping host response pathways in Lyme disease and West Nile virus infection. Front Immunol 2022; 13:1012824. [PMID: 36569838 PMCID: PMC9784464 DOI: 10.3389/fimmu.2022.1012824] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 11/07/2022] [Indexed: 12/14/2022] Open
Abstract
Advancement in proteomics methods for interrogating biological samples has helped identify disease biomarkers for early diagnostics and unravel underlying molecular mechanisms of disease. Herein, we examined the serum proteomes of 23 study participants presenting with one of two common arthropod-borne infections: Lyme disease (LD), an extracellular bacterial infection or West Nile virus infection (WNV), an intracellular viral infection. The LC/MS based serum proteomes of samples collected at the time of diagnosis and during convalescence were assessed using a depletion-based high-throughput shotgun proteomics (dHSP) pipeline as well as a non-depleting blotting-based low-throughput platform (MStern). The LC/MS integrated analyses identified host proteome responses in the acute and recovery phases shared by LD and WNV infections, as well as differentially abundant proteins that were unique to each infection. Notably, we also detected proteins that distinguished localized from disseminated LD and asymptomatic from symptomatic WNV infection. The proteins detected in both diseases with the dHSP pipeline identified unique and overlapping proteins detected with the non-depleting MStern platform, supporting the utility of both detection methods. Machine learning confirmed the use of the serum proteome to distinguish the infection from healthy control sera but could not develop discriminatory models between LD and WNV at current sample numbers. Our study is the first to compare the serum proteomes in two arthropod-borne infections and highlights the similarities in host responses even though the pathogens and the vectors themselves are different.
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Affiliation(s)
- Patrick Boada
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, CA, United States
| | - Benoit Fatou
- Department of Pathology, Boston Children’s Hospital - Harvard Medical School, Boston, MA, United States
- Precision Vaccines Program, Boston Children’s Hospital, Boston, MA, United States
| | - Alexia A. Belperron
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States
| | - Tara K. Sigdel
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, CA, United States
| | - Kinga K. Smolen
- Precision Vaccines Program, Boston Children’s Hospital, Boston, MA, United States
- Division of Infectious Diseases, Boston Children’s Hospital – Harvard Medical School, Boston, MA, United States
| | - Zainab Wurie
- Department of Pathology, Boston Children’s Hospital - Harvard Medical School, Boston, MA, United States
- Precision Vaccines Program, Boston Children’s Hospital, Boston, MA, United States
| | - Ofer Levy
- Precision Vaccines Program, Boston Children’s Hospital, Boston, MA, United States
- Division of Infectious Diseases, Boston Children’s Hospital – Harvard Medical School, Boston, MA, United States
- Broad Institute of Massachusetts Institute of Technology & Harvard, Cambridge, MA, United States
| | - Shannon E. Ronca
- Division of Tropical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
- William T. Shearer Center for Human Immunobiology, Texas Children’s Hospital, Houston, TX, United States
| | - Kristy O. Murray
- Division of Tropical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
- William T. Shearer Center for Human Immunobiology, Texas Children’s Hospital, Houston, TX, United States
| | - Juliane M. Liberto
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, CA, United States
| | - Priyanka Rashmi
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, CA, United States
| | - Maggie Kerwin
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, CA, United States
| | - Ruth R. Montgomery
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States
| | - Linda K. Bockenstedt
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States
| | - Hanno Steen
- Department of Pathology, Boston Children’s Hospital - Harvard Medical School, Boston, MA, United States
- Precision Vaccines Program, Boston Children’s Hospital, Boston, MA, United States
| | - Minnie M. Sarwal
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, CA, United States
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12
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Cooper O, Waespy M, Chen D, Kelm S, Li Q, Haselhorst T, Tiralongo J. Sugar-decorated carbon dots: a novel tool for targeting immunomodulatory receptors. NANOSCALE ADVANCES 2022; 4:5355-5364. [PMID: 36540112 PMCID: PMC9729803 DOI: 10.1039/d2na00364c] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 10/14/2022] [Indexed: 06/17/2023]
Abstract
Interactions between sialic acid (Sia) and sialic acid-binding immunoglobulin-like lectins (siglecs) regulate the immune system, with aberrations contributing to pathologies such as autoimmunity, infectious disease and cancer. Over the last decade, several multivalent Sia ligands have been synthesized to modulate the Sia-binding affinity of proteins/lectins. Here, we report a novel class of multivalent siglec probes through the decoration of α(2,6)-sialyllactose ligands on inherently fluorescent carbon dots (CD). We show that the preference of α(2,3)-linked Sia for siglec-1 can be altered by increasing the multivalence of Sia ligands present on the CD, and that a locally high glycan concentration can have a direct effect on linkage specificity. Additionally, micromolar (IC50 ∼ 70 μM) interaction of α(2,6)-sialyllactose-CD (6-CD) with siglec-2 (CD22) revealed it was capable of generating a significant cytotoxic effect on Burkitt's Lymphoma (BL) Daudi B cells. This phenonomen was attributed to 6-CD's ability to form trans interactions with CD22 on masked BL Daudi cells as a direct result of clustering of the Sia moiety on the CD surface. Overall, our glycoengineered carbon dots represent a novel high affinity molecular probe with multiple applications in sialoglycoscience and medicine.
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Affiliation(s)
- Oren Cooper
- Institute for Glycomics, Gold Coast Campus, Griffith University Queensland 4222 Australia
| | - Mario Waespy
- Centre for Biomolecular Interactions Bremen, Department of Biology and Chemistry, University of Bremen 28334 Bremen Germany
| | - Dechao Chen
- School of Engineering and Built Environment, Nathan Campus, Griffith University QLD 4111 Australia
| | - Sørge Kelm
- Centre for Biomolecular Interactions Bremen, Department of Biology and Chemistry, University of Bremen 28334 Bremen Germany
| | - Qin Li
- School of Engineering and Built Environment, Nathan Campus, Griffith University QLD 4111 Australia
- Queensland Micro- and Nanotechnology Centre, Australia, Nathan Campus, Griffith University QLD 4111 Australia
| | - Thomas Haselhorst
- Institute for Glycomics, Gold Coast Campus, Griffith University Queensland 4222 Australia
| | - Joe Tiralongo
- Institute for Glycomics, Gold Coast Campus, Griffith University Queensland 4222 Australia
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13
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Liu G, Hao M, Zeng B, Liu M, Wang J, Sun S, Liu C, Huilian C. Sialic acid and food allergies: The link between nutrition and immunology. Crit Rev Food Sci Nutr 2022; 64:3880-3906. [PMID: 36369942 DOI: 10.1080/10408398.2022.2136620] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Food allergies (FA), a major public health problem recognized by the World Health Organization, affect an estimated 3%-10% of adults and 8% of children worldwide. However, effective treatments for FA are still lacking. Recent advances in glycoimmunology have demonstrated the great potential of sialic acids (SAs) in the treatment of FA. SAs are a group of nine-carbon α-ketoacids usually linked to glycoproteins and glycolipids as terminal glycans. They play an essential role in modulating immune responses and may be an effective target for FA intervention. As exogenous food components, sialylated polysaccharides have anti-FA effects. In contrast, as endogenous components, SAs on immunoglobulin E and immune cell surfaces contribute to the pathogenesis of FA. Given the lack of comprehensive information on the effects of SAs on FA, we reviewed the roles of endogenous and exogenous SAs in the pathogenesis and treatment of FA. In addition, we considered the structure-function relationship of SAs to provide a theoretical basis for the development of SA-based FA treatments.
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Affiliation(s)
- Guirong Liu
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Mengzhen Hao
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Binghui Zeng
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Manman Liu
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Junjuan Wang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Shanfeng Sun
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Changqi Liu
- School of Exercise and Nutritional Sciences, College of Health and Human Services, San Diego State University, California, United States of America
| | - Che Huilian
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
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14
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Xiao X, Peng Y, Wang Z, Zhang L, Yang T, Sun Y, Chen Y, Zhang W, Chang X, Huang W, Tian S, Feng Z, Xinhua N, Tang Q, Mao Y. A novel immune checkpoint siglec-15 antibody inhibits LUAD by modulating mφ polarization in TME. Pharmacol Res 2022; 181:106269. [PMID: 35605813 DOI: 10.1016/j.phrs.2022.106269] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 05/10/2022] [Accepted: 05/18/2022] [Indexed: 12/22/2022]
Abstract
BACKGROUND Siglec-15 (S15) is a type-I transmembrane protein and is considered a new candidate of immune checkpoint inhibitor for cancer immunotherapy. METHODS In the present study, we first constructed and characterized a chimeric S15-specific monoclonal antibody (S15-4E6A). Then, the antitumor effectiveness and modulatory role of S15-4E6A in macrophages (mφs) were explored in vitro and in vivo. Finally, the underlying mechanism by which S15mAb inhibits LUAD was preliminarily explored. RESULTS The results demonstrated the successful construction of S15-4E6A, and S15-4E6A exerted an efficacious tumor-inhibitory effect on LUAD cells and xenografts. S15-4E6A could promote M1-mφ polarization while inhibiting M2-mφ polarization, both in vitro and in vivo. CONCLUSIONS S15-based immunotherapy that functions by modulating mφ polarization may be a promising strategy for the treatment of S15-positive LUAD.
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Affiliation(s)
- Xuejun Xiao
- Department of Pharmacology, Xinjiang Medical University, Urumqi, China
| | - Yan Peng
- NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Zheyue Wang
- NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Louqian Zhang
- Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Tingting Yang
- NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Yangyang Sun
- Department of Pathology, Changzhou No. 2 People's Hospital Affiliated with Nanjing Medical University, Changzhou, China
| | - Yufeng Chen
- NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Wenqing Zhang
- NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Xinxia Chang
- NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Wen Huang
- Department of Oncology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shuning Tian
- NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, Nanjing, China
| | - Zhenqing Feng
- NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Nabi Xinhua
- Department of Pharmacology, Xinjiang Medical University, Urumqi, China.
| | - Qi Tang
- NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, Nanjing, China; Department of Pathology, Changzhou No. 2 People's Hospital Affiliated with Nanjing Medical University, Changzhou, China.
| | - Yuan Mao
- Department of Oncology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of Oncology, Geriatric Hospital of Nanjing Medical University, Nanjing, China; Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.
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15
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Bjornsdottir G, Stefansdottir L, Thorleifsson G, Sulem P, Norland K, Ferkingstad E, Oddsson A, Zink F, Lund SH, Nawaz MS, Bragi Walters G, Skuladottir AT, Gudjonsson SA, Einarsson G, Halldorsson GH, Bjarnadottir V, Sveinbjornsson G, Helgadottir A, Styrkarsdottir U, Gudmundsson LJ, Pedersen OB, Hansen TF, Werge T, Banasik K, Troelsen A, Skou ST, Thørner LW, Erikstrup C, Nielsen KR, Mikkelsen S, Jonsdottir I, Bjornsson A, Olafsson IH, Ulfarsson E, Blondal J, Vikingsson A, Brunak S, Ostrowski SR, Ullum H, Thorsteinsdottir U, Stefansson H, Gudbjartsson DF, Thorgeirsson TE, Stefansson K. Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology. Nat Commun 2022; 13:634. [PMID: 35110524 PMCID: PMC8810832 DOI: 10.1038/s41467-022-28167-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 01/12/2022] [Indexed: 12/12/2022] Open
Abstract
Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10-39; ORdorsalgia = 0.92, P = 7.2 × 10-15) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10-11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Muhammad S Nawaz
- deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - G Bragi Walters
- deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | | | | | | | - Gisli H Halldorsson
- deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
- School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
| | | | | | | | | | | | - Ole B Pedersen
- Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Folkmann Hansen
- Danish Headache Center, Dept. Neurology, Rigshospitalet-Glostrup, Glostrup, Denmark
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Werge
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark
- Lundbeck Foundation for GeoGenetics, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark
| | - Karina Banasik
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anders Troelsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Orthopaedic Surgery, CAG ROAD-Research OsteoArthritis Denmark, Copenhagen University Hospital, Hvidovre, Denmark
| | - Soren T Skou
- Research Unit for Musculoskeletal Function and Physiotherapy, Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
- The Research Unit PROgrez, Department of Physiotherapy and Occupational Therapy, Næstved-Slagelse-Ringsted Hospitals, Næstved, Denmark
| | - Lise Wegner Thørner
- Department of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark
| | - Christian Erikstrup
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
| | - Kaspar Rene Nielsen
- Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark
| | - Susan Mikkelsen
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
| | - Ingileif Jonsdottir
- deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Aron Bjornsson
- Department of Neurosurgery, Landspitali University Hospital, Reykjavik, Iceland
| | - Ingvar H Olafsson
- Department of Neurosurgery, Landspitali University Hospital, Reykjavik, Iceland
| | - Elfar Ulfarsson
- Department of Neurosurgery, Landspitali University Hospital, Reykjavik, Iceland
| | - Josep Blondal
- Health Care Institution of West Iceland, Stykkisholmur, Iceland
| | | | - Soren Brunak
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sisse R Ostrowski
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark
| | - Henrik Ullum
- Statens Serum Institut, Copenhagen, Copenhagen, Denmark
| | - Unnur Thorsteinsdottir
- deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | | | - Daniel F Gudbjartsson
- deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
- School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
| | | | - Kari Stefansson
- deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
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16
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Tsuda E, Fukuda C, Okada A, Karibe T, Hiruma Y, Takagi N, Isumi Y, Yamamoto T, Hasegawa T, Uehara S, Koide M, Udagawa N, Amizuka N, Kumakura S. Characterization, pharmacokinetics, and pharmacodynamics of anti-Siglec-15 antibody and its potency for treating osteoporosis and as follow-up treatment after parathyroid hormone use. Bone 2022; 155:116241. [PMID: 34715394 DOI: 10.1016/j.bone.2021.116241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 10/21/2021] [Accepted: 10/21/2021] [Indexed: 11/15/2022]
Abstract
Recent studies have established the idea that Siglec-15 is involved in osteoclast differentiation and/or function, and it is anticipated that therapies suppressing Siglec-15 function can be used to treat bone diseases such as osteoporosis. We have produced rat monoclonal anti-Siglec-15 antibody (32A1) and successively generated humanized monoclonal anti-Siglec-15 antibody (DS-1501a) from 32A1. Studies on the biological properties of DS-1501a showed its specific binding affinity to Siglec-15 and strong activity to inhibit osteoclastogenesis. 32A1 inhibited multinucleation of osteoclasts and bone resorption (pit formation) in cultured mouse bone marrow cells. 32A1 also inhibited pit formation in cultured human osteoclast precursor cells. Maximum serum concentration and serum exposure of DS-1501a in rats were increased in a dose-dependent manner after single subcutaneous or intravenous administration. Furthermore, single administration of DS-1501a significantly suppressed bone resorption markers with minimal effects on bone formation markers and suppressed the decrease in bone mineral density (BMD) of the lumbar vertebrae in ovariectomized (OVX) rats. In histological analysis, the osteoclasts distant from the chondro-osseous junction of the tibia tended to be flattened, shrunken, and functionally impaired in 32A1-treated rats, while alkaline phosphatase-positive osteoblasts were observed throughout the metaphyseal trabeculae. In addition, we compared the efficacy of 32A1 with that of alendronate (ALN) as follow-up medicine after treatment with parathyroid hormone (PTH) using mature established osteoporosis rats. The beneficial effect of PTH on bone turnover disappeared 8 weeks after discontinuing the treatment. The administration of 32A1 once every 4 weeks for 8 weeks suppressed bone resorption and bone formation when the treatment was switched from PTH to 32A1, leading to the maintenance of BMD and bone strength. Unlike with ALN, the onset of suppression of bone resorption with 32A1 was rapid, while the suppression of bone formation was mild. The improvement of bone mass, beneficial bone turnover balance, and suppression of osteoclast differentiation/multinucleation achieved by 32A1 were supported by histomorphometry. Notably, the effects of 32A1 on bone strength, not only structural (extrinsic) but also material (intrinsic) properties, were significantly greater than those of ALN. Since the effect of 32A1 on BMD was moderate, its effect on bone strength could not be fully explained by the increase in BMD. The beneficial balance of bone turnover caused by 32A1 might, at least in part, be responsible for the improvement in bone quality. This is the first report describing the effects of anti-Siglec-15 antibody in OVX rats; the findings suggest that this antibody could be an excellent candidate for treating osteoporosis, especially in continuation therapy after PTH treatment, due to its rapid action and unprecedented beneficial effects on bone quality.
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Affiliation(s)
- Eisuke Tsuda
- Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Chie Fukuda
- Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
| | - Akiko Okada
- Biological Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Tsuyoshi Karibe
- Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Yoshiharu Hiruma
- Pharmacovigilance Department, Daiichi Sankyo Co., Ltd., 3-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8426, Japan
| | - Nana Takagi
- Pharmacovigilance Department, Daiichi Sankyo Co., Ltd., 3-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8426, Japan
| | - Yoshitaka Isumi
- Oncology Research Laboratories I, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Tomomaya Yamamoto
- Developmental Biology of Hard Tissue, Faculty of Dental Medicine, Nishi 7 Chome, Kita 13 Jo, Kita-ku, Sapporo, Hokkaido University, Hokkaido 060-8586, Japan
| | - Tomoka Hasegawa
- Developmental Biology of Hard Tissue, Faculty of Dental Medicine, Nishi 7 Chome, Kita 13 Jo, Kita-ku, Sapporo, Hokkaido University, Hokkaido 060-8586, Japan
| | - Shunsuke Uehara
- Department of Oral Biochemistry, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan
| | - Masanori Koide
- Division of Hard Tissue Research, Institute for Oral Science, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan
| | - Nobuyuki Udagawa
- Department of Oral Biochemistry, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan; Division of Hard Tissue Research, Institute for Oral Science, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan
| | - Norio Amizuka
- Developmental Biology of Hard Tissue, Faculty of Dental Medicine, Nishi 7 Chome, Kita 13 Jo, Kita-ku, Sapporo, Hokkaido University, Hokkaido 060-8586, Japan
| | - Seiichiro Kumakura
- Translational Medicine Function, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
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17
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Tvaroška I. Glycosyltransferases as targets for therapeutic intervention in cancer and inflammation: molecular modeling insights. CHEMICAL PAPERS 2022. [DOI: 10.1007/s11696-021-02026-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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18
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Tian L, Lei A, Tan T, Zhu M, Zhang L, Mou H, Zhang J. Macrophage-Based Combination Therapies as a New Strategy for Cancer Immunotherapy. KIDNEY DISEASES (BASEL, SWITZERLAND) 2022; 8:26-43. [PMID: 35224005 DOI: 10.1159/000518664] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 07/16/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Cells of the immune system can inhibit tumor growth and progression; however, immune cells can also promote tumor cell growth, survival, and angiogenesis as a result of the immunosuppressive microenvironments. In the last decade, a growing number of new therapeutic strategies focused on reversing the immunosuppressive status of tumor microenvironments (TMEs), to reprogram the TME to be normal, and to further activate the antitumor functions of immune cells. Most of the "hot tumors" are encompassed with M2 macrophages promoting tumor growth, and the accumulation of M2 macrophages into tumor islets leads to poor prognosis in a wide variety of tumors. SUMMARY Therefore, how to uncover more immunosuppressive signals and to reverse the M2 tumor-associated macrophages (TAMs) to M1-type macrophages is essential for reversing the immunosuppressive state. Except for reeducation of TAMs in the cancer immunotherapy, macrophages as central effectors and regulators of the innate immune system have the capacity of phagocytosis and immune modulation in macrophage-based cell therapies. KEY MESSAGES We review the current macrophage-based cell therapies that use genetic engineering to augment macrophage functionalities with antitumor activity for the application of novel genetically engineered immune cell therapeutics. A combination of TAM reeducation and macrophage-based cell strategy may bring us closer to achieving the original goals of curing cancer. In this review, we describe the characteristics, immune status, and tumor immunotherapy strategies of macrophages to provide clues and evidences for future macrophage-based immune cell therapies.
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Affiliation(s)
- Lin Tian
- Department of Basic Medical Sciences, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Anhua Lei
- Department of Basic Medical Sciences, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Tianyu Tan
- Department of Basic Medical Sciences, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Mengmeng Zhu
- Department of Basic Medical Sciences, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Li Zhang
- Department of Basic Medical Sciences, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Haibo Mou
- Department of Medical Oncology, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou, China
| | - Jin Zhang
- Department of Basic Medical Sciences, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, China
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19
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Rashid S, Song D, Yuan J, Mullin BH, Xu J. Molecular structure, expression, and the emerging role of Siglec-15 in skeletal biology and cancer. J Cell Physiol 2021; 237:1711-1719. [PMID: 34893976 DOI: 10.1002/jcp.30654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/12/2021] [Accepted: 11/18/2021] [Indexed: 12/25/2022]
Abstract
Siglec-15, a Siglec family member and type-1 transmembrane protein, is expressed mainly in human macrophages and dendritic cells. It is comprised of a lysine-containing transmembrane domain, two extracellular immunoglobulin (Ig)-like domains and a short cytoplasmic domain. Siglec-15 is highly conserved in vertebrates and acts as an immunoreceptor. It exerts diverse functions on osteoclast physiology as well as the tumor microenvironment. Siglec-15 interacts with adapter protein DAP12 - Syk signaling pathway to regulate the RANKL/RANK-mediated PI3K, AKT, and ERK signaling pathways during osteoclast formation in vitro. Consistently, the lack of the Siglec-15 gene in mice leads to impaired osteoclast activity and osteopetrosis in vivo. In addition, Siglec-15 is expressed by tumor-associated macrophages (TAMs) and regulates the tumor microenvironment by activating the SYK/MAPK signaling pathway. Interestingly, Siglec-15 shares sequence homology to programmed death-ligand 1 (PD-L1) and has a potential immune-regulatory role in cancer immunology. Thus, Siglec-15 might also represent an alternative target for the treatment of cancers that do not respond to anti-PD-L1/PD-1 immunotherapy. Understanding the role of Siglec-15 in osteoclastogenesis and the tumor microenvironment will help us to develop new treatments for bone disorders and cancer.
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Affiliation(s)
- Sarah Rashid
- School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia
| | - Dezhi Song
- School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia.,Research Centre for Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Jinbo Yuan
- School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia
| | - Benjamin H Mullin
- School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia.,Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
| | - Jiake Xu
- School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia
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20
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Jarahian M, Marofi F, Maashi MS, Ghaebi M, Khezri A, Berger MR. Re-Expression of Poly/Oligo-Sialylated Adhesion Molecules on the Surface of Tumor Cells Disrupts Their Interaction with Immune-Effector Cells and Contributes to Pathophysiological Immune Escape. Cancers (Basel) 2021; 13:5203. [PMID: 34680351 PMCID: PMC8534074 DOI: 10.3390/cancers13205203] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/28/2022] Open
Abstract
Glycans linked to surface proteins are the most complex biological macromolecules that play an active role in various cellular mechanisms. This diversity is the basis of cell-cell interaction and communication, cell growth, cell migration, as well as co-stimulatory or inhibitory signaling. Our review describes the importance of neuraminic acid and its derivatives as recognition elements, which are located at the outermost positions of carbohydrate chains linked to specific glycoproteins or glycolipids. Tumor cells, especially from solid tumors, mask themselves by re-expression of hypersialylated neural cell adhesion molecule (NCAM), neuropilin-2 (NRP-2), or synaptic cell adhesion molecule 1 (SynCAM 1) in order to protect themselves against the cytotoxic attack of the also highly sialylated immune effector cells. More particularly, we focus on α-2,8-linked polysialic acid chains, which characterize carrier glycoproteins such as NCAM, NRP-2, or SynCam-1. This characteristic property correlates with an aggressive clinical phenotype and endows them with multiple roles in biological processes that underlie all steps of cancer progression, including regulation of cell-cell and/or cell-extracellular matrix interactions, as well as increased proliferation, migration, reduced apoptosis rate of tumor cells, angiogenesis, and metastasis. Specifically, re-expression of poly/oligo-sialylated adhesion molecules on the surface of tumor cells disrupts their interaction with immune-effector cells and contributes to pathophysiological immune escape. Further, sialylated glycoproteins induce immunoregulatory cytokines and growth factors through interactions with sialic acid-binding immunoglobulin-like lectins. We describe the processes, which modulate the interaction between sialylated carrier glycoproteins and their ligands, and illustrate that sialic acids could be targets of novel therapeutic strategies for treatment of cancer and immune diseases.
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Affiliation(s)
- Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy Unit Heidelberg, 69120 Heidelberg, Germany;
| | - Faroogh Marofi
- Department of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5165665931, Iran;
| | - Marwah Suliman Maashi
- Stem Cells and Regenerative Medicine Unit at King Fahad Medical Research Centre, Jeddah 11211, Saudi Arabia;
| | - Mahnaz Ghaebi
- Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan 4513956184, Iran;
| | - Abdolrahman Khezri
- Department of Biotechnology, Inland Norway University of Applied Sciences, 2418 Hamar, Norway;
| | - Martin R. Berger
- German Cancer Research Center, Toxicology and Chemotherapy Unit Heidelberg, 69120 Heidelberg, Germany;
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21
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Qiu H, Liu C, Huang M, Shen S, Wang W. Prognostic Value of Combined CA19-9 with Aspartate Aminotransferase to Lymphocyte Ratio in Patients with Intrahepatic Cholangiocarcinoma After Hepatectomy. Cancer Manag Res 2021; 13:5969-5980. [PMID: 34377017 PMCID: PMC8349206 DOI: 10.2147/cmar.s320380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 07/16/2021] [Indexed: 02/05/2023] Open
Abstract
Purpose The prognosis of intrahepatic cholangiocarcinoma (ICC) patients after surgical resection remains poor. Effective prognostic biomarkers are expected to stratify ICC patients and optimize their treatment strategies. To investigate the prognostic value of carbohydrate antigen 19-9 (CA19-9), aspartate aminotransferase to lymphocyte ratio index (ALRI), and their combination (CAC) in predicting long-term outcomes in ICC patients after hepatectomy. Patients and Methods ICC patients underwent initial hepatectomy for curative purpose from January 2009 to September 2017 were reviewed retrospectively. Area under the receiver operating characteristics curve (AUC) was used to distinguish the identification effectiveness of three different measures. Kaplan–Meier curves and Cox proportional hazards regression were used to assess the value of preoperative CAC grade in predicting overall survival (OS) and disease-free survival (DFS). Results A total of 530 patients were included and randomly divided into two groups (derivation cohort and validation cohort). During a median follow-up of 18 months (1–115.4 months), 317 patients (59.8%) died and 381 patients (71.9%) developed tumor recurrence. Lower ALRI, decreased serum CA19-9 level and CAC grade were found to be associated with better OS and DFS (both P<0.001). Importantly, the AUC for CAC grade was significantly greater than ALRI and CA19-9. In addition, results from Cox proportional hazards regression from both cohorts suggest that tumor number, node invasion, and CAC grade as independent prognostic factors for both OS and DFS. Conclusion This study demonstrated that CAC grade is a valuable biomarker for the prognosis of ICC patients. Specifically, patients with elevated CAC grades were correlated to worse long-term outcome after the hepatectomy. Our data suggest that increased CAC grades can be used to stratify patients and help to decide their treatment strategies.
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Affiliation(s)
- Haizhou Qiu
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Chang Liu
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Min Huang
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Shu Shen
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Wentao Wang
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
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22
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Zhou ZR, Wang XY, Jiang L, Li DW, Qian RC. Sialidase-Conjugated "NanoNiche" for Efficient Immune Checkpoint Blockade Therapy. ACS APPLIED BIO MATERIALS 2021; 4:5735-5741. [PMID: 35006749 DOI: 10.1021/acsabm.1c00507] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Reactivation of T-cell immunity by blocking the PD-1/PD-L1 immune checkpoint has been considered a promising strategy for cancer treatment. However, the recognition of PD-L1 by antibodies is usually suppressed due to the N-linked glycosylation of PD-L1. In this study, we present an effective PD-L1-blocking strategy based on a sialidase-conjugated "NanoNiche" to improve the antitumor effect via T-cell reactivation. Molecularly imprinted by PD-L1 N-glycans, NanoNiche can specifically recognize glycosylated PD-L1 on the tumor cell surface, thereby resulting in more efficient PD-L1 blockade. Moreover, sialidase modified on the surface of NanoNiche can selectively strip sialoglycans from tumor cells, enhancing immune cell infiltration. In vitro studies confirmed that NanoNiche can specifically bind with PD-L1 while also desialylate the tumor cell surface. The proliferation of PD-L1-positive MDA-MB-231 human breast cancer cells under T-cell killing was significantly inhibited after NanoNiche treatment. In vivo experiments in solid tumors show enhanced therapeutic efficacy. Thus, the NanoNiche-sialidase conjugate represents a promising approach for immune checkpoint blockade therapy.
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Affiliation(s)
- Ze-Rui Zhou
- Key Laboratory for Advanced Materials, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, P. R. China
| | - Xiao-Yuan Wang
- Key Laboratory for Advanced Materials, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, P. R. China
| | - Lei Jiang
- Key Laboratory for Advanced Materials, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, P. R. China
| | - Da-Wei Li
- Key Laboratory for Advanced Materials, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, P. R. China
| | - Ruo-Can Qian
- Key Laboratory for Advanced Materials, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, P. R. China
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23
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Reporter cell assay for human CD33 validated by specific antibodies and human iPSC-derived microglia. Sci Rep 2021; 11:13462. [PMID: 34188106 PMCID: PMC8242067 DOI: 10.1038/s41598-021-92434-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 06/07/2021] [Indexed: 12/15/2022] Open
Abstract
CD33/Sialic acid-binding Ig-like lectin 3 (SIGLEC3) is an innate immune receptor expressed on myeloid cells and mediates inhibitory signaling via tyrosine phosphatases. Variants of CD33 are associated with Alzheimer’s disease (AD) suggesting that modulation of CD33 signaling might be beneficial in AD. Hence, there is an urgent need for reliable cellular CD33 reporter systems. Therefore, we generated a CD33 reporter cell line expressing a fusion protein consisting of the extracellular domain of either human full-length CD33 (CD33M) or the AD-protective variant CD33ΔE2 (D2-CD33/CD33m) linked to TYRO protein tyrosine kinase binding protein (TYROBP/DAP12) to investigate possible ligands and antibodies for modulation of CD33 signaling. Application of the CD33-specific antibodies P67.6 and 1c7/1 to the CD33M-DAP12 reporter cells resulted in increased phosphorylation of the kinase SYK, which is downstream of DAP12. CD33M-DAP12 but not CD33ΔE2-DAP12 expressing reporter cells showed increased intracellular calcium levels upon treatment with CD33 antibody P67.6 and partially for 1c7/1. Furthermore, stimulation of human induced pluripotent stem cell-derived microglia with the CD33 antibodies P67.6 or 1c7/1 directly counteracted the triggering receptor expressed on myeloid cells 2 (TREM2)-induced phosphorylation of SYK and decreased the phagocytic uptake of bacterial particles. Thus, the developed reporter system confirmed CD33 pathway activation by CD33 antibody clones P67.6 and 1c7/1. In addition, data showed that phosphorylation of SYK by TREM2 activation and phagocytosis of bacterial particles can be directly antagonized by CD33 signaling.
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24
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Zhang H, Xie Y, Hu Z, Yu H, Xie X, Ye Y, Xu W, Nian S, Yuan Q. Integrative Analysis of the Expression of SIGLEC Family Members in Lung Adenocarcinoma via Data Mining. Front Oncol 2021; 11:608113. [PMID: 33796453 PMCID: PMC8008066 DOI: 10.3389/fonc.2021.608113] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 02/22/2021] [Indexed: 12/25/2022] Open
Abstract
Background: Sialic acid-binding immunoglobulin-type lectin (SIGLEC) family members are involved in regulating immune-cell activation, proliferation, and apoptosis, and they play an important role in tumor development. However, their expression and correlation with immune molecules in lung adenocarcinoma (LUAD) remain unclear. Methods: We utilized Gene Expression Profiling Interactive Analysis, Kaplan-Meier analysis, the limma package in R/Bioconductor, the University of California Santa Cruz Cancer Genome Browser, cBioPortal, STRING, Cytoscape, DAVID, and the Tumor Immune Estimation Resource for gene and protein profiling and analyses. Results: The results showed that SIGLEC10 and SIGLEC15 levels were upregulated in LUAD, whereas SIGLEC1, CD22 (SIGLEC2), CD33, myelin-associated glycoprotein (SIGLEC4), SIGLEC5, SIGLEC6, SIGLEC7, SIGLEC8, SIGLEC11, and SIGLEC14 levels were significantly downregulated, with their low expression associated with poor overall survival. Moreover, we observed high SIGLEC-mutation rates (22%) in LUAD patients, with SIGLEC functions determined as primarily involved in regulating the immune response, signal transduction, inflammatory response, and cell adhesion. Furthermore, we found that SIGLEC expression was significantly correlated with immune-cell infiltration, especially macrophages, neutrophils, and dendritic cells, and highly associated with immune molecules such as CD80, CD86, CD28, B-cell-activating factor, programmed cell death 1 ligand 2, and colony stimulating factor 1 receptor. Conclusion: These results provide insight into the potential molecular mechanism associated with SIGLEC-related development of LUAD, as well as clues for screening biomarkers and therapeutic targets.
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Affiliation(s)
- Haiyan Zhang
- Public Experimental Technology Center, The School of Basic Medical Science, Southwest Medical University, Luzhou, China
| | - Yongfei Xie
- Life Sciences School, Anhui Agricultural University, Hefei, China
| | - Zhi Hu
- Department of Thoracic Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Hong Yu
- Public Experimental Technology Center, The School of Basic Medical Science, Southwest Medical University, Luzhou, China
| | - Xiang Xie
- Public Experimental Technology Center, The School of Basic Medical Science, Southwest Medical University, Luzhou, China
| | - Yingchun Ye
- Public Experimental Technology Center, The School of Basic Medical Science, Southwest Medical University, Luzhou, China
| | - Wenfeng Xu
- Public Experimental Technology Center, The School of Basic Medical Science, Southwest Medical University, Luzhou, China
| | - Siji Nian
- Public Experimental Technology Center, The School of Basic Medical Science, Southwest Medical University, Luzhou, China
| | - Qing Yuan
- Public Experimental Technology Center, The School of Basic Medical Science, Southwest Medical University, Luzhou, China
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25
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Wißfeld J, Nozaki I, Mathews M, Raschka T, Ebeling C, Hornung V, Brüstle O, Neumann H. Deletion of Alzheimer's disease-associated CD33 results in an inflammatory human microglia phenotype. Glia 2021; 69:1393-1412. [PMID: 33539598 DOI: 10.1002/glia.23968] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 01/05/2021] [Accepted: 01/08/2021] [Indexed: 12/13/2022]
Abstract
Genome-wide association studies demonstrated that polymorphisms in the CD33/sialic acid-binding immunoglobulin-like lectin 3 gene are associated with late-onset Alzheimer's disease (AD). CD33 is expressed on myeloid immune cells and mediates inhibitory signaling through protein tyrosine phosphatases, but the exact function of CD33 in microglia is still unknown. Here, we analyzed CD33 knockout human THP1 macrophages and human induced pluripotent stem cell-derived microglia for immunoreceptor tyrosine-based activation motif pathway activation, cytokine transcription, phagocytosis, and phagocytosis-associated oxidative burst. Transcriptome analysis of the macrophage lines showed that knockout of CD33 as well as knockdown of the CD33 signaling-associated protein tyrosine phosphatase, nonreceptor type 6 (PTPN6) led to constitutive activation of inflammation-related pathways. Moreover, deletion of CD33 or expression of Exon 2-deleted CD33 (CD33ΔE2 /CD33m) led to increased phosphorylation of the kinases spleen tyrosine kinase (SYK) and extracellular signal-regulated kinase 1 and 2 (ERK1 and 2). Transcript analysis by quantitative real-time polymerase chain reaction confirmed increased levels of interleukin (IL) 1B, IL8, and IL10 after knockout of CD33 in macrophages and microglia. In addition, upregulation of the gene transcripts of the AD-associated phosphatase INPP5D was observed after knockout of CD33. Functional analysis of macrophages and microglia showed that phagocytosis of aggregated amyloid-β1-42 and bacterial particles were increased after knockout of CD33 or CD33ΔE2 expression and knockdown of PTPN6. Furthermore, the phagocytic oxidative burst during uptake of amyloid-β1-42 or bacterial particles was increased after CD33 knockout but not in CD33ΔE2 -expressing microglia. In summary, deletion of CD33 or expression of CD33ΔE2 in human macrophages and microglia resulted in putative beneficial phagocytosis of amyloid β1-42 , but potentially detrimental oxidative burst and inflammation, which was absent in CD33ΔE2 -expressing microglia.
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Affiliation(s)
- Jannis Wißfeld
- Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany
| | - Ichiro Nozaki
- Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany.,Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Mona Mathews
- Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany.,LIFE & BRAIN GmbH, Cellomics Unit, Bonn, Germany
| | - Tamara Raschka
- Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing, Sankt Augustin, Germany
| | - Christian Ebeling
- Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing, Sankt Augustin, Germany
| | - Veit Hornung
- Institute of Molecular Medicine, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany
| | - Oliver Brüstle
- Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany.,LIFE & BRAIN GmbH, Cellomics Unit, Bonn, Germany
| | - Harald Neumann
- Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany
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26
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Raposo CD, Canelas AB, Barros MT. Human Lectins, Their Carbohydrate Affinities and Where to Find Them. Biomolecules 2021; 11:188. [PMID: 33572889 PMCID: PMC7911577 DOI: 10.3390/biom11020188] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/02/2021] [Accepted: 01/26/2021] [Indexed: 12/20/2022] Open
Abstract
Lectins are a class of proteins responsible for several biological roles such as cell-cell interactions, signaling pathways, and several innate immune responses against pathogens. Since lectins are able to bind to carbohydrates, they can be a viable target for targeted drug delivery systems. In fact, several lectins were approved by Food and Drug Administration for that purpose. Information about specific carbohydrate recognition by lectin receptors was gathered herein, plus the specific organs where those lectins can be found within the human body.
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Affiliation(s)
- Cláudia D. Raposo
- LAQV-Requimte, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal;
| | - André B. Canelas
- Glanbia-AgriChemWhey, Lisheen Mine, Killoran, Moyne, E41 R622 Tipperary, Ireland;
| | - M. Teresa Barros
- LAQV-Requimte, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal;
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27
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Murugesan G, Correia VG, Palma AS, Chai W, Li C, Feizi T, Martin E, Laux B, Franz A, Fuchs K, Weigle B, Crocker PR. Siglec-15 recognition of sialoglycans on tumor cell lines can occur independently of sialyl Tn antigen expression. Glycobiology 2021; 31:44-54. [PMID: 32501471 PMCID: PMC7799145 DOI: 10.1093/glycob/cwaa048] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/21/2020] [Accepted: 06/01/2020] [Indexed: 12/15/2022] Open
Abstract
Siglec-15 is a conserved sialic acid-binding Ig-like lectin expressed on osteoclast progenitors, which plays an important role in osteoclast development and function. It is also expressed by tumor-associated macrophages and by some tumors, where it is thought to contribute to the immunosuppressive microenvironment. It was shown previously that engagement of macrophage-expressed Siglec-15 with tumor cells expressing its ligand, sialyl Tn (sTn), triggered production of TGF-β. In the present study, we have further investigated the interaction between Siglec-15 and sTn on tumor cells and its functional consequences. Based on binding assays with lung and breast cancer cell lines and glycan-modified cells, we failed to see evidence for recognition of sTn by Siglec-15. However, using a microarray of diverse, structurally defined glycans, we show that Siglec-15 binds with higher avidity to sialylated glycans other than sTn or related antigen sequences. In addition, we were unable to demonstrate enhanced TGF-β secretion following co-culture of Siglec-15-expressing monocytic cell lines with tumor cells expressing sTn or following Siglec-15 cross-linking with monoclonal antibodies. However, we did observe activation of the SYK/MAPK signaling pathway following antibody cross-linking of Siglec-15 that may modulate the functional activity of macrophages.
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Affiliation(s)
- Gavuthami Murugesan
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom
| | - Viviana G Correia
- Applied Molecular Biosciences Unit, Faculty of Science and Technology, NOVA University of Lisbon, Lisbon, Portugal
| | - Angelina S Palma
- Applied Molecular Biosciences Unit, Department of Chemistry, Faculty of Science and Technology, NOVA University of Lisbon, Lisbon, Portugal
| | - Wengang Chai
- Glycosciences Laboratory, Imperial College London, London, United Kingdom
| | - Chunxia Li
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy and Shandong Provincial Key laboratory of Glycoscience and Glycoengineering, Ocean University of China, Qingdao 266003, China
| | - Ten Feizi
- Glycosciences Laboratory, Imperial College London, London, United Kingdom
| | - Eva Martin
- Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Str. 65, 88397 Biberach/Riss, Germany
| | - Brigitte Laux
- Cancer Immunology & Immune Modulation, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Str. 65, 88397 Biberach/Riss, Germany
| | - Alexandra Franz
- Cancer Immunology & Immune Modulation, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Str. 65, 88397 Biberach/Riss, Germany
| | - Klaus Fuchs
- Biotherapeutics Discovery, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Str. 65, 88397 Biberach/Riss, Germany
| | - Bernd Weigle
- Cancer Immunology & Immune Modulation, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Str. 65, 88397 Biberach/Riss, Germany
| | - Paul R Crocker
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom
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28
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Functions and therapeutic targets of Siglec-mediated infections, inflammations and cancers. J Formos Med Assoc 2021; 120:5-24. [DOI: 10.1016/j.jfma.2019.10.019] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 06/11/2019] [Accepted: 10/28/2019] [Indexed: 12/20/2022] Open
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29
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Pleass RJ. The therapeutic potential of sialylated Fc domains of human IgG. MAbs 2021; 13:1953220. [PMID: 34288809 PMCID: PMC8296966 DOI: 10.1080/19420862.2021.1953220] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/08/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Pathogens frequently use multivalent binding to sialic acid to infect cells or to modulate immunity through interactions with human sialic acid-binding immunoglobulin-type lectins (Siglecs). Molecules that interfere with these interactions could be of interest as diagnostics, anti-infectives or as immune modulators. This review describes the development of molecular scaffolds based on the crystallizable fragment (Fc) region of immunoglobulin (Ig) G that deliver high-avidity binding to innate immune receptors, including sialic acid-dependent receptors. The ways in which the sialylated Fc may be engineered as immune modulators that mimic the anti-inflammatory properties of intravenous polyclonal Ig or as blockers of sialic-acid-dependent infectivity by viruses are also discussed.
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Affiliation(s)
- Richard J. Pleass
- Department of Tropical Disease Biology, Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UK
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30
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Chen Z, Yu M, Guo L, Zhang B, Liu S, Zhang W, Zhou B, Yan J, Ma Q, Yang Z, Xiao Y, Xu Y, Li H, Ye Q. Tumor Derived SIGLEC Family Genes May Play Roles in Tumor Genesis, Progression, and Immune Microenvironment Regulation. Front Oncol 2020; 10:586820. [PMID: 33240817 PMCID: PMC7681003 DOI: 10.3389/fonc.2020.586820] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 10/06/2020] [Indexed: 12/24/2022] Open
Abstract
Background SIGLEC family genes can also be expressed on tumor cells in different cancer types, and though it has been found that SIGLEC genes expressed by immune cells can be exploited by tumors to escape immune surveillance, functions of tumor derived SIGLEC expression in tumor microenvironment (TME) were barely investigated, which could play roles in cancer patients' survival. Methods Using bioinformatic analysis, mutation status of SIGLEC family genes was explored through the cBioPortal database, and expression of them in different tumors was explored through the UALCAN database. The GEPIA database was used to compare SIGLEC family genes' mRNA between cancers and to generate a highly correlated gene list in tumors. A KM-plotter database was used to find the association between SIGLEC genes and survival of patients. The associations between SIGLEC family genes' expression, immune infiltration, and immune regulators' expression in TME were generated and examined by the TIMER 2.0 database; the differential fold changes of SIGLEC family genes in specific oncogenic mutation groups of different cancer types were also yielded by TIMER 2.0. The networks of SIGLEC family genes and highly correlated genes were constructed by the STRING database, and gene ontology and pathway annotation of SIGLEC family highly correlated genes were performed through the DAVID database. Results SIGLEC family genes were highly mutated and amplified in melanoma, endometrial carcinoma, non-small cell lung cancer, bladder urothelial carcinoma, and esophagogastric adenocarcinoma, while deep deletion of SIGLEC family genes was common in diffuse glioma. Alteration of SIGLEC family genes demonstrated different levels in specific tumors, and oncogenic mutation in different cancer types could influence SIGLEC family genes' expression. Most SIGLEC family genes were related to patients' overall survival and progression free survival. Also, tumor derived SIGLEC family genes were related to tumor immune cell infiltration and may regulate TME by influencing chemokine axis. Conclusion Our computational analysis showed SIGLEC family genes expressed by tumor cells were associated with tumor behaviors, and they may also influence TME through chemokine axis, playing vital roles in patients' survival. Further experiments targeting tumor derived SIGLEC family genes are needed to confirm their influences on tumor growth, metastasis, and immune environment regulation.
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Affiliation(s)
- Zheng Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Mincheng Yu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Lei Guo
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Bo Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Shuang Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Wentao Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Binghai Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Jiuliang Yan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Qianni Ma
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Zhangfu Yang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Yongsheng Xiao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Yongfeng Xu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Hui Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Qinghai Ye
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
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Wu Y, Yang D, Liu R, Wang L, Chen GY. Selective Response to Bacterial Infection by Regulating Siglec-E Expression. iScience 2020; 23:101473. [PMID: 32889432 PMCID: PMC7479279 DOI: 10.1016/j.isci.2020.101473] [Citation(s) in RCA: 4] [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: 04/08/2020] [Revised: 07/10/2020] [Accepted: 08/11/2020] [Indexed: 12/24/2022] Open
Abstract
Interactions between microbes and hosts can be a benign, deleterious, or even fatal, resulting in death of the host, the microbe, or both. Sialic acid-binding immunoglobulin-like lectins (Siglecs) suppress infection responses to sialylated pathogens. However, most pathogens are nonsialylated. Here we determined Siglecs respond to nonsialylated Gram-negative bacteria (Escherichia coli 25922 and DH5α) and Gram-positive bacteria (Staphylococcus aureus and Listeria monocytogenes). We found that Siglece-/- mice had higher mortality than wild-type mice following Gram-negative but not Gram-positive bacterial infection. Better survival in wild-type mice depended on more efficient clearance of Gram-negative than Gram-positive bacteria. Gram-negative bacteria upregulated Siglec-E, thus increasing reactive oxygen species (ROS); Tyr432 in the ITIM domain of Siglec-E was required to increase ROS. Moreover, Gram-negative bacteria upregulated Siglec-E via TLR4/MyD88/JNK/NF-κB/AP-1, whereas Gram-positive bacteria downregulated Siglec-E via TLR2/RANKL/TRAF6/Syk. Thus, our study describes a fundamentally new role for Siglec-E during infection.
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Affiliation(s)
- Yin Wu
- Children's Foundation Research Institute at Le Bonheur Children's Hospital, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA
| | - Darong Yang
- Children's Foundation Research Institute at Le Bonheur Children's Hospital, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA
| | - Runhua Liu
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lizhong Wang
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Guo-Yun Chen
- Children's Foundation Research Institute at Le Bonheur Children's Hospital, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA
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Kroezen BS, Conti G, Girardi B, Cramer J, Jiang X, Rabbani S, Müller J, Kokot M, Luisoni E, Ricklin D, Schwardt O, Ernst B. A Potent Mimetic of the Siglec-8 Ligand 6'-Sulfo-Sialyl Lewis x. ChemMedChem 2020; 15:1706-1719. [PMID: 32744401 DOI: 10.1002/cmdc.202000417] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Indexed: 12/15/2022]
Abstract
Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6'-sulfo-sialyl Lewisx has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6'-sulfo-sialyl Lewisx and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved.
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Affiliation(s)
- Blijke S Kroezen
- Molecular Pharmacy Group Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Gabriele Conti
- Molecular Pharmacy Group Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Benedetta Girardi
- Molecular Pharmacy Group Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Jonathan Cramer
- Molecular Pharmacy Group Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Xiaohua Jiang
- Molecular Pharmacy Group Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Said Rabbani
- Molecular Pharmacy Group Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Jennifer Müller
- Molecular Pharmacy Group Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Maja Kokot
- Molecular Pharmacy Group Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Enrico Luisoni
- Molecular Pharmacy Group Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Daniel Ricklin
- Molecular Pharmacy Group Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Oliver Schwardt
- Molecular Pharmacy Group Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
| | - Beat Ernst
- Molecular Pharmacy Group Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland
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Interferon-α alters host glycosylation machinery during treated HIV infection. EBioMedicine 2020; 59:102945. [PMID: 32827942 PMCID: PMC7452630 DOI: 10.1016/j.ebiom.2020.102945] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/19/2020] [Accepted: 07/22/2020] [Indexed: 12/17/2022] Open
Abstract
Background A comprehensive understanding of host factors modulated by the antiviral cytokine interferon-α (IFNα) is imperative for harnessing its beneficial effects while avoiding its detrimental side-effects during HIV infection. Cytokines modulate host glycosylation which plays a critical role in mediating immunological functions. However, the impact of IFNα on host glycosylation has never been characterized. Methods We assessed the impact of pegylated IFNα2a on IgG glycome, as well as CD8+ T and NK cell-surface glycomes, of 18 HIV-infected individuals on suppressive antiretroviral therapy. We linked these glycomic signatures to changes in inflammation, CD8+ T and NK cell phenotypes, and HIV DNA. Findings We identified significant interactions that support a model in which a) IFNα increases the proportion of pro-inflammatory, bisecting GlcNAc glycans (known to enhance FcγR binding) within the IgG glycome, which in turn b) increases inflammation, which c) leads to poor CD8+ T cell phenotypes and poor IFNα-mediated reduction of HIV DNA. Examining cell-surface glycomes, IFNα increases levels of the immunosuppressive GalNAc-containing glycans (T/Tn antigens) on CD8+ T cells. This induction is associated with lower HIV-gag-specific CD8+ T cell functions. Last, IFNα increases levels of fucose on NK cells. This induction is associated with higher NK functions upon K562 stimulation. Interpretation IFNα causes host glycomic alterations that are known to modulate immunological responses. These alterations are associated with both detrimental and beneficial consequences of IFNα. Manipulating host glycomic interactions may represent a strategy for enhancing the positive effects of IFNα while avoiding its detrimental side-effects. Funding NIH grants R21AI143385, U01AI110434.
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34
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Pirgova G, Chauveau A, MacLean AJ, Cyster JG, Arnon TI. Marginal zone SIGN-R1 + macrophages are essential for the maturation of germinal center B cells in the spleen. Proc Natl Acad Sci U S A 2020; 117:12295-12305. [PMID: 32424104 PMCID: PMC7275705 DOI: 10.1073/pnas.1921673117] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The mechanisms that regulate germinal center (GC) B cell responses in the spleen are not fully understood. Here we use a combination of pharmacologic and genetic approaches to delete SIGN-R1+ marginal zone (MZ) macrophages and reveal their specific contribution to the regulation of humoral immunity in the spleen. We find that while SIGN-R1+ macrophages were not essential for initial activation of B cells, they were required for maturation of the response and development of GC B cells. These defects could be corrected when follicular helper T (Tfh) cells were induced before macrophage ablation or when Tfh responses were enhanced. Moreover, we show that in the absence of SIGN-R1+ macrophages, DCIR2+ dendritic cells (DCs), which play a key role in priming Tfh responses, were unable to cluster to the interfollicular regions of the spleen and were instead displaced to the MZ. Restoring SIGN-R1+ macrophages to the spleen corrected positioning of DCIR2+ DCs and rescued the GC B cell response. Our study reveals a previously unappreciated role for SIGN-R1+ macrophages in regulation of the GC reaction and highlights the functional specification of macrophage subsets in the MZ compartment.
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Affiliation(s)
- Gabriela Pirgova
- Kennedy Institute of Rheumatology, University of Oxford, OX3 7FY Oxford, United Kingdom
| | - Anne Chauveau
- Kennedy Institute of Rheumatology, University of Oxford, OX3 7FY Oxford, United Kingdom
| | - Andrew J MacLean
- Kennedy Institute of Rheumatology, University of Oxford, OX3 7FY Oxford, United Kingdom
| | - Jason G Cyster
- Howard Hughes Medical Institute, University of California, San Francisco, CA 94143
- Department of Microbiology and Immunology, University of California, San Francisco, CA 94143
| | - Tal I Arnon
- Kennedy Institute of Rheumatology, University of Oxford, OX3 7FY Oxford, United Kingdom;
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35
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Meyer SJ, Böser A, Korn MA, Koller C, Bertocci B, Reimann L, Warscheid B, Nitschke L. Cullin 3 Is Crucial for Pro-B Cell Proliferation, Interacts with CD22, and Controls CD22 Internalization on B Cells. THE JOURNAL OF IMMUNOLOGY 2020; 204:3360-3374. [DOI: 10.4049/jimmunol.1900925] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 04/03/2020] [Indexed: 12/15/2022]
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36
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Characterisation of the Dynamic Interactions between Complex
N
‐Glycans and Human CD22. Chembiochem 2019; 21:129-140. [DOI: 10.1002/cbic.201900295] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Indexed: 12/21/2022]
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37
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Tecle E, Reynoso HS, Wang R, Gagneux P. The female reproductive tract contains multiple innate sialic acid-binding immunoglobulin-like lectins (Siglecs) that facilitate sperm survival. J Biol Chem 2019; 294:11910-11919. [PMID: 31201275 PMCID: PMC6682739 DOI: 10.1074/jbc.ra119.008729] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 05/27/2019] [Indexed: 12/15/2022] Open
Abstract
A sperm that fertilizes an egg has successfully survived multiple checkpoints within the female reproductive tract, termed pre-fertilization events. The leukocytic response is a pre-fertilization event in which sperm trigger an immune response that promotes homing of circulating leukocytes to the uterine lumen to destroy most sperm. Various glycoconjugates decorate the sperm surface, including sialic acids, which are abundant at the sperm surface where they cap most glycan chains and regulate sperm migration through cervical mucus, formation of the sperm oviductal reservoir, and sperm capacitation. However, the role of sperm-associated sialic acids in the leukocytic reaction remains unknown. The cognate endogenous binding partners of sialic acids, sialic acid-binding immunoglobulin-like lectins (Siglecs) play a pivotal role in regulating many immune responses. Here we investigated whether sperm-associated sialic acids inhibit activation of neutrophils, one of the major immune cells involved in the leukocytic reaction. We used in vitro interactions between sperm and neutrophils as well as binding assays between sperm and recombinant Siglec-Fc chimeric proteins to measure interactions. Moreover, we examined whether Siglecs are expressed on human and mouse endometria, which have a role in initiating the leukocytic reaction. Surprisingly less sialylated, capacitated, sperm did not increase neutrophil activation in vitro However, we observed expression of several Siglecs on the endometrium and that these receptors interact with sialylated sperm. Our results indicate that sperm sialic acids may interact with endometrial Siglecs and that these interactions facilitate sperm survival in the face of female immunity.
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Affiliation(s)
- Eillen Tecle
- Department of Pathology, Glycobiology Research and Training Center, University of California San Diego, San Diego, California 92093
| | - Hector Sequoyah Reynoso
- Department of Pathology, Glycobiology Research and Training Center, University of California San Diego, San Diego, California 92093
| | - Ruixuan Wang
- Department of Pathology, Glycobiology Research and Training Center, University of California San Diego, San Diego, California 92093
| | - Pascal Gagneux
- Department of Pathology, Glycobiology Research and Training Center, University of California San Diego, San Diego, California 92093
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38
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Lübbers J, Rodríguez E, van Kooyk Y. Modulation of Immune Tolerance via Siglec-Sialic Acid Interactions. Front Immunol 2018; 9:2807. [PMID: 30581432 PMCID: PMC6293876 DOI: 10.3389/fimmu.2018.02807] [Citation(s) in RCA: 174] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 11/14/2018] [Indexed: 12/11/2022] Open
Abstract
One of the key features of the immune system is its extraordinary capacity to discriminate between self and non-self and to respond accordingly. Several molecular interactions allow the induction of acquired immune responses when a foreign antigen is recognized, while others regulate the resolution of inflammation, or the induction of tolerance to self-antigens. Post-translational signatures, such as glycans that are part of proteins (glycoproteins) and lipids (glycolipids) of host cells or pathogens, are increasingly appreciated as key molecules in regulating immunity vs. tolerance. Glycans are sensed by glycan binding receptors expressed on immune cells, such as C-type lectin receptors (CLRs) and Sialic acid binding immunoglobulin type lectins (Siglecs), that respond to specific glycan signatures by triggering tolerogenic or immunogenic signaling pathways. Glycan signatures present on healthy tissue, inflamed and malignant tissue or pathogens provide signals for “self” or “non-self” recognition. In this review we will focus on sialic acids that serve as “self” molecular pattern ligands for Siglecs. We will emphasize on the function of Siglec-expressing mononuclear phagocytes as sensors for sialic acids in tissue homeostasis and describe how the sialic acid-Siglec axis is exploited by tumors and pathogens for the induction of immune tolerance. Furthermore, we highlight how the sialic acid-Siglec axis can be utilized for clinical applications to induce or inhibit immune tolerance.
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Affiliation(s)
- Joyce Lübbers
- Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands
| | - Ernesto Rodríguez
- Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands
| | - Yvette van Kooyk
- Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands
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39
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Corfield AP. The Interaction of the Gut Microbiota with the Mucus Barrier in Health and Disease in Human. Microorganisms 2018; 6:microorganisms6030078. [PMID: 30072673 PMCID: PMC6163557 DOI: 10.3390/microorganisms6030078] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 07/25/2018] [Accepted: 07/30/2018] [Indexed: 02/07/2023] Open
Abstract
Glycoproteins are major players in the mucus protective barrier in the gastrointestinal and other mucosal surfaces. In particular the mucus glycoproteins, or mucins, are responsible for the protective gel barrier. They are characterized by their high carbohydrate content, present in their variable number, tandem repeat domains. Throughout evolution the mucins have been maintained as integral components of the mucosal barrier, emphasizing their essential biological status. The glycosylation of the mucins is achieved through a series of biosynthetic pathways processes, which generate the wide range of glycans found in these molecules. Thus mucins are decorated with molecules having information in the form of a glycocode. The enteric microbiota interacts with the mucosal mucus barrier in a variety of ways in order to fulfill its many normal processes. How bacteria read the glycocode and link to normal and pathological processes is outlined in the review.
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Affiliation(s)
- Anthony P Corfield
- Mucin Research Group, School of Clinical Sciences, Bristol Royal Infirmary, Level 7, Marlborough Street, Bristol BS2 8HW, UK.
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40
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Wang MM, Miao D, Cao XP, Tan L, Tan L. Innate immune activation in Alzheimer's disease. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:177. [PMID: 29951499 DOI: 10.21037/atm.2018.04.20] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Alzheimer's disease (AD) is known as the most predominant cause of dementia among the aged people. Previously, two hallmarks of AD pathology including extracellular amyloid-β (Aβ) deposition and neurofibrillary tangles (NFTs) inside neurons have been identified. With a better understanding of this disease, neuroinflammation has been a focus, and as its initial event, innate immune activation plays an indispensable role. In brain, as an endogenous stimulator, extracellular Aβ deposition activates innate immunity through binding to the pattern recognition receptors (PRR), thus leading to the production and release of substantial inflammatory mediators (NO and ROS) and cytokines (IL-1β, IL-10, IL-33 and TNF-α) contributing to the development of AD. Epidemiologic evidence has suggested an affirmative influence of non-steroidal anti-inflammatory drugs (NSAIDs) on delaying the progression of AD. Therefore, blocking the inflammatory process may be an effective way to delay or even cure AD. In this review, we mainly elucidate the mechanism underlying these immune responses in AD pathogenesis and attempt to seek the therapeutic methods targeting neuroinflammation.
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Affiliation(s)
- Ming-Ming Wang
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Dan Miao
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Xi-Peng Cao
- Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Lin Tan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Lan Tan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
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41
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Jones MB. IgG and leukocytes: Targets of immunomodulatory α2,6 sialic acids. Cell Immunol 2018; 333:58-64. [PMID: 29685495 DOI: 10.1016/j.cellimm.2018.03.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 03/30/2018] [Indexed: 12/27/2022]
Abstract
ST6Gal1 is a critical sialyltransferase enzyme that controls the addition of α2,6-linked sialic acids to the termini of glycans. Attachment of sialic acids to glycoproteins as a posttranslational modification influences cellular responses, and is a well-known modifier of immune cell behavior. ST6Gal1 activity impacts processes such as: effector functions of immunoglobulin G via Fc sialylation, hematopoietic capacity by hematopoietic stem and progenitor cell surface sialylation, and lymphocyte activation thresholds though CD22 engagement and inhibition of galectins. This review summarizes recent studies that suggest α2,6 sialylation by ST6Gal1 has an immunoregulatory effect on immune reactions.
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Affiliation(s)
- Mark B Jones
- Case Western Reserve University, School of Medicine, Department of Pathology, Cleveland, OH 44106, United States.
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42
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Silva M, Silva Z, Marques G, Ferro T, Gonçalves M, Monteiro M, van Vliet SJ, Mohr E, Lino AC, Fernandes AR, Lima FA, van Kooyk Y, Matos T, Tadokoro CE, Videira PA. Sialic acid removal from dendritic cells improves antigen cross-presentation and boosts anti-tumor immune responses. Oncotarget 2018; 7:41053-41066. [PMID: 27203391 PMCID: PMC5173042 DOI: 10.18632/oncotarget.9419] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 04/16/2016] [Indexed: 12/18/2022] Open
Abstract
Dendritic cells (DCs) hold promise for anti-cancer immunotherapy. However, clinically, their efficiency is limited and novel strategies to improve DC-mediated anti-tumor responses are needed. Human DCs display high content of sialic acids, which inhibits their maturation and co-stimulation capacity. Here, we aimed to understand whether exogenous desialylation of DCs improves their anti-tumor immunity. Compared to fully sialylated DCs, desialylated human DCs loaded with tumor-antigens showed enhanced ability to induce autologous T cells to proliferate, to secrete Th1 cytokines, and to specifically induce tumor cell apoptosis. Desialylated DCs showed an increased expression of MHC-I and -II, co-stimulatory molecules and an augmented secretion of IL-12. Desialylated HLA-A*02:01 DCs pulsed with gp100 peptides displayed enhanced peptide presentation through MHC-I, resulting in higher activation ofgp100280–288 specific CD8+ cytotoxic T cells. Desialylated murine DCs also exhibited increased MHC and co-stimulatory molecules and higher antigen cross-presentation via MHC-I. These DCs showed higher ability to activate antigen-specific CD4+ and CD8+ T cells, and to specifically induce tumor cell apoptosis. Collectively, our data demonstrates that desialylation improves DCs' ability to elicit T cell-mediated anti-tumor activity, due to increased MHC-I expression and higher antigen presentation via MHC-I. Sialidase treatment of DCs may represent a technology to improve the efficacy of antigen loaded-DC-based vaccines for anti-cancer immunotherapy.
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Affiliation(s)
- Mariana Silva
- CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal
| | - Zélia Silva
- CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.,UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Portugal
| | - Graça Marques
- CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal
| | - Tiago Ferro
- CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.,UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Portugal
| | - Márcia Gonçalves
- CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal
| | - Mauro Monteiro
- CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal
| | - Sandra J van Vliet
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Elodie Mohr
- IGC, Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | | | - Alexandra R Fernandes
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Portugal.,CQE, Centro Química Estrutural, Instituto Superior Técnico, ULisboa, Lisboa, Portugal
| | - Flávia A Lima
- CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal
| | - Yvette van Kooyk
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | | | - Carlos E Tadokoro
- Universidade Vila Velha, Espírito Santo, Brasil.,IGC, Instituto Gulbenkian de Ciência, Oeiras, Portugal.,UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Portugal
| | - Paula A Videira
- CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.,UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Portugal
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Zhang W, Ambikan AT, Sperk M, van Domselaar R, Nowak P, Noyan K, Russom A, Sönnerborg A, Neogi U. Transcriptomics and Targeted Proteomics Analysis to Gain Insights Into the Immune-control Mechanisms of HIV-1 Infected Elite Controllers. EBioMedicine 2018; 27:40-50. [PMID: 29269040 PMCID: PMC5828548 DOI: 10.1016/j.ebiom.2017.11.031] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 11/22/2017] [Accepted: 11/30/2017] [Indexed: 12/21/2022] Open
Abstract
A small subset of HIV-1 infected individuals, the "Elite Controllers" (EC), can control viral replication and restrain progression to immunodeficiency without antiretroviral therapy (ART). In this study, a cross-sectional transcriptomics and targeted proteomics analysis were performed in a well-defined Swedish cohort of untreated EC (n=19), treatment naïve patients with viremia (VP, n=32) and HIV-1-negative healthy controls (HC, n=23). The blood transcriptome identified 151 protein-coding genes that were differentially expressed (DE) in VP compared to EC. Genes like CXCR6 and SIGLEC1 were downregulated in EC compared to VP. A definite distinction in gene expression between males and females among all patient-groups were observed. The gene expression profile between female EC and the healthy females was similar but did differ between male EC and healthy males. At targeted proteomics analysis, 90% (29/32) of VPs clustered together while EC and HC clustered separately from VP. Among the soluble factors, 33 were distinctive to be statistically significant (False discovery rate=0.02). Cell surface receptor signaling pathway, programmed cell death, response to cytokine and cytokine-mediated signaling seem to synergistically play an essential role in HIV-1 control in EC.
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Affiliation(s)
- Wang Zhang
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Science for Life Laboratory, Division of Proteomics and Nanobiotechnology, KTH Royal Institute of Technology, Solna, Stockholm, Sweden
| | - Anoop T Ambikan
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Maike Sperk
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Faculty of Medicine, University of Tuebingen, Tuebingen, Germany
| | - Robert van Domselaar
- Department of Medicine Huddinge, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Piotr Nowak
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Medicine Huddinge, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Kajsa Noyan
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Aman Russom
- Science for Life Laboratory, Division of Proteomics and Nanobiotechnology, KTH Royal Institute of Technology, Solna, Stockholm, Sweden
| | - Anders Sönnerborg
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Medicine Huddinge, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Ujjwal Neogi
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Science for Life Laboratory, Division of Proteomics and Nanobiotechnology, KTH Royal Institute of Technology, Solna, Stockholm, Sweden.
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44
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Genetics of Alzheimer's disease: From pathogenesis to clinical usage. J Clin Neurosci 2017; 45:1-8. [PMID: 28869135 DOI: 10.1016/j.jocn.2017.06.074] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 06/19/2017] [Indexed: 01/27/2023]
Abstract
Alzheimer's disease (AD) is the most common type of dementia and has caused a major global health concern. Understanding the etiology of AD can be beneficial for the diagnosis and intervention of this disease. Genetics plays a vital role in the pathogenesis of AD. Research methods in genetics such as the linkage analysis, study of candidate genes, genome-wide association study (GWAS), and next-generation sequencing (NGS) technology help us map the genetic information in AD, which can not only provide a new insight into the pathogenesis of AD but also be beneficial for early targeted intervention of AD. This review summarizes the pathogenesis as well as the diagnostic and therapeutic value of genetics in AD.
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45
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Li YQ, Zhang J, Li J, Sun L. First characterization of fish CD22: An inhibitory role in the activation of peripheral blood leukocytes. Vet Immunol Immunopathol 2017; 190:39-44. [DOI: 10.1016/j.vetimm.2017.07.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 06/24/2017] [Accepted: 07/11/2017] [Indexed: 01/05/2023]
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Xie J, Christiaens I, Yang B, Breedam WV, Cui T, Nauwynck HJ. Molecular cloning of porcine Siglec-3, Siglec-5 and Siglec-10, and identification of Siglec-10 as an alternative receptor for porcine reproductive and respiratory syndrome virus (PRRSV). J Gen Virol 2017; 98:2030-2042. [PMID: 28742001 PMCID: PMC5656783 DOI: 10.1099/jgv.0.000859] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
In recent years, several entry mediators have been characterized for porcine
reproductive and respiratory syndrome virus (PRRSV). Porcine sialoadhesin [pSn,
also known as sialic acid-binding immunoglobulin-type lectin (Siglec-1)] and
porcine CD163 (pCD163) have been identified as the most important host entry
mediators that can fully coordinate PRRSV infection into macrophages. However,
recent isolates have not only shown a tropism for sialoadhesin-positive cells,
but also for sialoadhesin-negative cells. This observation might be partly
explained by the existence of additional receptors that can support PRRSV
binding and entry. In the search for new receptors, recently identified porcine
Siglecs (Siglec-3, Siglec-5 and Siglec-10), members of the same family as
sialoadhesin, were cloned and characterized. Only Siglec-10 was able to
significantly improve PRRSV infection and production in a CD163-transfected cell
line. Compared with sialoadhesin, Siglec-10 performed equally effectively as a
receptor for PRRSV type 2 strain MN-184, but it was less capable of supporting
infection with PRRSV type 1 strain LV (Lelystad virus). Siglec-10 was
demonstrated to be involved in the endocytosis of PRRSV, confirming the
important role of Siglec-10 in the entry process of PRRSV. In conclusion, it can
be stated that PRRSV may use several Siglecs to enter macrophages, which may
explain the strain differences in the pathogenesis.
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Affiliation(s)
- Jiexiong Xie
- Laboratory of Virology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium
| | - Isaura Christiaens
- Laboratory of Virology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium
| | - Bo Yang
- Laboratory of Virology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium
| | - Wander Van Breedam
- Unit for Medical Biotechnology, Medical Biotechnology Center, VIB, Technologiepark 927, B-9052 Ghent, Belgium
| | - Tingting Cui
- Laboratory of Virology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium
| | - Hans J Nauwynck
- Laboratory of Virology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium
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47
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Erythrocyte sialoglycoproteins engage Siglec-9 on neutrophils to suppress activation. Blood 2017; 129:3100-3110. [PMID: 28416510 DOI: 10.1182/blood-2016-11-751636] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 04/04/2017] [Indexed: 12/13/2022] Open
Abstract
Healthy blood neutrophils are functionally quiescent in the bloodstream, have a short lifespan, and exit the circulation to carry out innate immune functions, or undergo rapid apoptosis and macrophage-mediated clearance to mitigate host tissue damage. Limitation of unnecessary intravascular neutrophil activation is also important to prevent serious inflammatory pathologies. Because neutrophils become easily activated after purification, we carried out ex vivo comparisons with neutrophils maintained in whole blood. We found a difference in activation state, with purified neutrophils showing signs of increased reactivity: shedding of l-selectin, CD11b upregulation, increased oxidative burst, and faster progression to apoptosis. We discovered that erythrocytes suppressed neutrophil activation ex vivo and in vitro, including reduced l-selectin shedding, oxidative burst, chemotaxis, neutrophil extracellular trap formation, bacterial killing, and induction of apoptosis. Selective and specific modification of sialic acid side chains on erythrocyte surfaces with mild sodium metaperiodate oxidation followed by aldehyde quenching with 4-methyl-3-thiosemicarbazide reduced neutrophil binding to erythrocytes and restored neutrophil activation. By enzyme-linked immunosorbent assay and immunofluorescence, we found that glycophorin A, the most abundant sialoglycoprotein on erythrocytes, engaged neutrophil Siglec-9, a sialic acid-recognizing receptor known to dampen innate immune cell activation. These studies demonstrate a previously unsuspected role for erythrocytes in suppressing neutrophils ex vivo and in vitro and help explain why neutrophils become easily activated after separation from whole blood. We propose that a sialic acid-based "self-associated molecular pattern" on erythrocytes also helps maintain neutrophil quiescence in the bloodstream. Our findings may be relevant to some prior experimental and clinical studies of neutrophils.
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Mikulak J, Di Vito C, Zaghi E, Mavilio D. Host Immune Responses in HIV-1 Infection: The Emerging Pathogenic Role of Siglecs and Their Clinical Correlates. Front Immunol 2017; 8:314. [PMID: 28386256 PMCID: PMC5362603 DOI: 10.3389/fimmu.2017.00314] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 03/06/2017] [Indexed: 11/25/2022] Open
Abstract
A better understanding of the mechanisms employed by HIV-1 to escape immune responses still represents one of the major tasks required for the development of novel therapeutic approaches targeting a disease still lacking a definitive cure. Host innate immune responses against HIV-1 are key in the early phases of the infection as they could prevent the development and the establishment of two hallmarks of the infection: chronic inflammation and viral reservoirs. Sialic acid-binding immunoglobulin-like lectins (Siglecs) belong to a family of transmembrane proteins able to dampen host immune responses and set appropriate immune activation thresholds upon ligation with their natural ligands, the sialylated carbohydrates. This immune-modulatory function is also targeted by many pathogens that have evolved to express sialic acids on their surface in order to escape host immune responses. HIV-1 envelope glycoprotein 120 (gp120) is extensively covered by carbohydrates playing active roles in life cycle of the virus. Indeed, besides forming a protecting shield from antibody recognition, this coat of N-linked glycans interferes with the folding of viral glycoproteins and enhances virus infectivity. In particular, the sialic acid residues present on gp120 can bind Siglec-7 on natural killer and monocytes/macrophages and Siglec-1 on monocytes/macrophages and dendritic cells. The interactions between these two members of the Siglec family and the sialylated glycans present on HIV-1 envelope either induce or increase HIV-1 entry in conventional and unconventional target cells, thus contributing to viral dissemination and disease progression. In this review, we address the impact of Siglecs in the pathogenesis of HIV-1 infection and discuss how they could be employed as clinic and therapeutic targets.
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Affiliation(s)
- Joanna Mikulak
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Italy; Istituto di Ricerca Genetica e Biomedica, UOS di Milano, Consiglio Nazionale delle Ricerche (UOS/IRGB/CNR), Rozzano, Italy
| | - Clara Di Vito
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center , Rozzano , Italy
| | - Elisa Zaghi
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center , Rozzano , Italy
| | - Domenico Mavilio
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Italy; Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Milan, Italy
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Human milk oligosaccharides: The role in the fine-tuning of innate immune responses. Carbohydr Res 2016; 432:62-70. [PMID: 27448325 DOI: 10.1016/j.carres.2016.07.009] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 07/05/2016] [Accepted: 07/06/2016] [Indexed: 01/12/2023]
Abstract
In order to secure the health of newborns over the period of immune immaturity during the first months of life, a mother provides her offspring with passive protection: bioactive molecules transferred through the placenta and breast milk. It is well known that human milk contains immunoglobulins (Ig), immune cells and diverse cytokines, which affect newborn directly or indirectly and contribute to the maturation of the immune system. However, in addition to the above-stated molecules, human milk oligosaccharides (HMOs), a complex mixture of free indigestible carbohydrates with multiple functions, play exceptional roles in the functioning of the infants' immune system. These biological molecules have been studied over decades, however, interest in HMOs does not seem to have abated. Although biological activities of oligosaccharides from human milk have been explicitly reviewed, information regarding the role of HMOs in inflammation remains rather fragmented. The purpose of this review is to compile existing knowledge about the role of certain species of HMOs, including fucosylated, galactosylated and sialylated oligosaccharides, and their signaling pathways in immunity and inflammation. The advances in applying this information to the treatment of diseases in infants as well as adults were also reviewed here.
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50
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Schmitt H, Sell S, Koch J, Seefried M, Sonnewald S, Daniel C, Winkler TH, Nitschke L. Siglec-H protects from virus-triggered severe systemic autoimmunity. J Exp Med 2016; 213:1627-44. [PMID: 27377589 PMCID: PMC4986536 DOI: 10.1084/jem.20160189] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 05/13/2016] [Indexed: 12/23/2022] Open
Abstract
Siglec-H is a key negative regulator of the type I interferon pathway, reducing the incidence of autoimmunity after viral infection. It is controversial whether virus infections can contribute to the development of autoimmune diseases. Type I interferons (IFNs) are critical antiviral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus. Type I IFN is mainly produced by plasmacytoid dendritic cells (pDCs). The secretion of type I IFN of pDCs is modulated by Siglec-H, a DAP12-associated receptor on pDCs. In this study, we show that Siglec-H–deficient pDCs produce more of the type I IFN, IFN-α, in vitro and that Siglec-H knockout (KO) mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo. This did not impact control of viral replication. Remarkably, several weeks after a single mCMV infection, Siglec-H KO mice developed a severe form of systemic lupus–like autoimmune disease with strong kidney nephritis. In contrast, uninfected aging Siglec-H KO mice developed a mild form of systemic autoimmunity. The induction of systemic autoimmune disease after virus infection in Siglec-H KO mice was accompanied by a type I IFN signature and fully dependent on type I IFN signaling. These results show that Siglec-H normally serves as a modulator of type I IFN responses after infection with a persistent virus and thereby prevents induction of autoimmune disease.
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Affiliation(s)
- Heike Schmitt
- Division of Genetics, Department of Biology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Sabrina Sell
- Nikolaus-Fiebiger-Zentrum, Division of Genetics, Department of Biology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Julia Koch
- Division of Genetics, Department of Biology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Martina Seefried
- Nikolaus-Fiebiger-Zentrum, Division of Genetics, Department of Biology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Sophia Sonnewald
- Division of Biochemistry, Department of Biology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Christoph Daniel
- Department of Nephropathology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Thomas H Winkler
- Nikolaus-Fiebiger-Zentrum, Division of Genetics, Department of Biology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Lars Nitschke
- Division of Genetics, Department of Biology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany
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