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Serrano-Regal MP, Camacho-Toledano C, Alonso-García I, Ortega MC, Machín-Díaz I, Lebrón-Galán R, García-Arocha J, Calahorra L, Nieto-Díaz M, Clemente D. Circulating myeloid-derived suppressor cell load and disease severity are associated to an enhanced oligodendroglial production in a murine model of multiple sclerosis. Neurobiol Dis 2025; 210:106919. [PMID: 40250717 DOI: 10.1016/j.nbd.2025.106919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/14/2025] [Accepted: 04/16/2025] [Indexed: 04/20/2025] Open
Abstract
Multiple sclerosis (MS) is a highly heterogeneous immune-mediated demyelinating disease. Myelin restoration is essential to prevent disability progression in MS patients. However, remyelinating therapies are failing in clinical trials, in part, due to the lack of biomarkers that classify the differing endogenous regenerative capacities of enrolled patients. In the experimental autoimmune encephalomyelitis (EAE) MS model, circulating monocytic myeloid-derived suppressor cells (M-MDSCs) are associated to milder disease courses, better recovery and less degree of tissue damage. Here, we show that disease severity affects the gradient of oligodendrocyte precursor cells (OPCs) present in mixed active-inactive lesions of MS patients, along with a positive correlation between M-MDSC density and OPC abundance. EAE disease severity negatively influences the density of total and newly generated OPCs found associated to the demyelinated lesions. In addition, disease severity also impacts the abundance of newly generated oligodendrocytes throughout the EAE disease course. Interestingly, circulating M-MDSCs at EAE onset and peak of the disease are directly associated to a higher density of newly generated oligodendrocytes in the demyelinated lesions. Our results set the basis for further studies on M-MDSCs as a promising new biomarker that identify a CNS prone to new oligodendrocyte generation in response to an inflammatory insult.
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Affiliation(s)
- Mari Paz Serrano-Regal
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain; Neuroimmune-Repair Group, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM). Spain
| | - Celia Camacho-Toledano
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain; Neuroimmune-Repair Group, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM). Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Avd. Monforte de Lemos, 3-5, 28029 Madrid, Spain
| | - Inmaculada Alonso-García
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain; Neuroimmune-Repair Group, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM). Spain
| | - María Cristina Ortega
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain; Neuroimmune-Repair Group, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM). Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Avd. Monforte de Lemos, 3-5, 28029 Madrid, Spain
| | - Isabel Machín-Díaz
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain; Neuroimmune-Repair Group, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM). Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Avd. Monforte de Lemos, 3-5, 28029 Madrid, Spain
| | - Rafael Lebrón-Galán
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - Jénnifer García-Arocha
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - Leticia Calahorra
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain; Neuroimmune-Repair Group, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM). Spain
| | - Manuel Nieto-Díaz
- Molecular Neuroprotection Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain; Molecular Neuroprotection Group, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM). Spain
| | - Diego Clemente
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain; Neuroimmune-Repair Group, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM). Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Avd. Monforte de Lemos, 3-5, 28029 Madrid, Spain.
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Wang W, Cao C, Pandian VD, Ye H, Chen H, Zhang L. Mac-1 regulates disease stage-specific immunosuppression via the nitric oxide pathway in autoimmune disease. SCIENCE ADVANCES 2025; 11:eads3728. [PMID: 40344054 PMCID: PMC12063669 DOI: 10.1126/sciadv.ads3728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Accepted: 04/03/2025] [Indexed: 05/11/2025]
Abstract
Integrin Mac-1 plays a critical role in the development of multiple sclerosis (MS); however, the underlying mechanism is not fully understood. Here, we developed a myeloid-specific Mac-1-deficient mouse. Using an experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we report that Mac-1 on myeloid cells is key to disease development. Our data reveal that myeloid-specific Mac-1 significantly increases EAE severity and hinders disease regression. Loss of Mac-1 increases Gr-1+ cells in peripheral tissues and the CNS and preferably accelerates the transition of Ly6Chi monocytes from a pro-inflammatory to an immunosuppressive phenotype in a disease stage-dependent manner. Mechanistically, our results demonstrate that Mac-1 suppresses interferon-γ production and prevents monocytes from acquiring immunosuppressive functions by reducing the expression of iNOS, IDO, and CD84. Administration of a NOS-specific inhibitor in Mac-1-deficient EAE mice abolishes disease regression. These insights could help develop Mac-1-targeting strategies for better treatment of MS.
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MESH Headings
- Animals
- Mice
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Encephalomyelitis, Autoimmune, Experimental/genetics
- Nitric Oxide/metabolism
- Macrophage-1 Antigen/metabolism
- Macrophage-1 Antigen/genetics
- Disease Models, Animal
- Mice, Knockout
- Multiple Sclerosis/immunology
- Multiple Sclerosis/metabolism
- Multiple Sclerosis/pathology
- Signal Transduction
- Monocytes/metabolism
- Monocytes/immunology
- Mice, Inbred C57BL
- Immune Tolerance
- Female
- Autoimmune Diseases/metabolism
- Autoimmune Diseases/immunology
- Autoimmune Diseases/pathology
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Affiliation(s)
- Wei Wang
- Department of Physiology, Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, USA
| | - Chunzhang Cao
- Department of Physiology, Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, USA
| | - Vishnuprabu Durairaj Pandian
- Department of Physiology, Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, USA
| | - Haofeng Ye
- Johns Hopkins Advanced Academic Programs, Johns Hopkins University of Arts and Sciences, Baltimore, MD, USA
| | - Hongxia Chen
- Department of Physiology, Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, USA
| | - Li Zhang
- Department of Physiology, Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, USA
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3
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Rodriguez S, Couloume L, Ferrant J, Vince N, Mandon M, Jean R, Monvoisin C, Leonard S, Le Gallou S, Silva NSB, Bourguiba-Hachemi S, Laplaud D, Garcia A, Casey R, Zephir H, Kerbrat A, Edan G, Lepage E, Thouvenot E, Ruet A, Mathey G, Gourraud PA, Tarte K, Delaloy C, Amé P, Roussel M, Michel L. Blood immunophenotyping of multiple sclerosis patients at diagnosis identifies a classical monocyte subset associated to disease evolution. Front Immunol 2025; 15:1494842. [PMID: 39845960 PMCID: PMC11751469 DOI: 10.3389/fimmu.2024.1494842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 12/03/2024] [Indexed: 01/24/2025] Open
Abstract
Introduction Myeloid cells trafficking from the periphery to the central nervous system are key players in multiple sclerosis (MS) through antigen presentation, cytokine secretion and repair processes. Methods Combination of mass cytometry on blood cells from 60 MS patients at diagnosis and 29 healthy controls, along with single cell RNA sequencing on paired blood and cerebrospinal fluid (CSF) samples from 5 MS patients were used for myeloid cells detailing. Results Myeloid compartment study demonstrated an enrichment of a peculiar classical monocyte population in 22% of MS patients at the time of diagnosis. Notably, this patients' subgroup exhibited a more aggressive disease phenotype two years post-diagnosis. This monocytic population, detected in both the CSF and blood, was characterized by CD206, CD209, CCR5 and CCR2 expression, and was found to be more frequent in MS patients carrying the HLA-DRB1*15:01 allele. Furthermore, pathways analysis predicted that these cells had antigen presentation capabilities coupled with pro-inflammatory phenotype. Discussion Altogether, these results point toward the amplification of a specific and pathogenic myeloid cell subset in MS patients with genetic susceptibilities.
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Affiliation(s)
- Stéphane Rodriguez
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, LabEx IGO, Rennes, France
- Pole Biologie-Centre Hospitalier Universitaire (CHU) Rennes, Rennes, France
| | - Laura Couloume
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, LabEx IGO, Rennes, France
| | - Juliette Ferrant
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, LabEx IGO, Rennes, France
- Pole Biologie-Centre Hospitalier Universitaire (CHU) Rennes, Rennes, France
| | - Nicolas Vince
- Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Marion Mandon
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, LabEx IGO, Rennes, France
- Pole Biologie-Centre Hospitalier Universitaire (CHU) Rennes, Rennes, France
| | - Rachel Jean
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, LabEx IGO, Rennes, France
- Pole Biologie-Centre Hospitalier Universitaire (CHU) Rennes, Rennes, France
| | - Celine Monvoisin
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, LabEx IGO, Rennes, France
| | - Simon Leonard
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, LabEx IGO, Rennes, France
| | - Simon Le Gallou
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, LabEx IGO, Rennes, France
- Pole Biologie-Centre Hospitalier Universitaire (CHU) Rennes, Rennes, France
| | - Nayane S. B. Silva
- Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
- São Paulo State University, Molecular Genetics and Bioinformatics Laboratory, School of Medicine, Botucatu, Brazil
| | - Sonia Bourguiba-Hachemi
- Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - David Laplaud
- Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
- Service de Neurologie, Centre Hospitalier Universitaire (CHU) Nantes, CRC-SEP Pays de la Loire, CIC 1413, Nantes, France
| | - Alexandra Garcia
- Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Romain Casey
- Lyon University, University Claude Bernard Lyon 1, Lyon, France
- Hospices Civils de Lyon, Neurology Department, Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, Bron, France
- Observatoire Français de la Sclérose en Plaques, Centre de Recherche en Neurosciences de Lyon, INSERM 1028 and CNRS UMR 5292, Lyon, France
- EUGENE DEVIC EDMUS Foundation against Multiple Sclerosis, State-Approved Foundation, Bron, France
| | - Helene Zephir
- Lille University, Inserm U1172, Lille University Hospital, Lille, France
| | - Anne Kerbrat
- Neurology Department, Rennes Clinical Investigation Centre, Rennes University Hospital-Rennes University-Institut National de la Santé et de la Recherche Médicale (INSERM), Rennes, France
| | - Gilles Edan
- Neurology Department, Rennes Clinical Investigation Centre, Rennes University Hospital-Rennes University-Institut National de la Santé et de la Recherche Médicale (INSERM), Rennes, France
| | - Emmanuelle Lepage
- Neurology Department, Rennes Clinical Investigation Centre, Rennes University Hospital-Rennes University-Institut National de la Santé et de la Recherche Médicale (INSERM), Rennes, France
| | - Eric Thouvenot
- Department of Neurology, Nimes University Hospital, Nimes, France
- Institut de Génomique Fonctionnelle, UMR5203, Inserm 1191, Université de Montpellier, Montpellier, France
| | - Aurelie Ruet
- Neurocentre Magendie, Institut National de la Santé et de la Recherche Médicale (INSERM) U1215, Bordeaux, France
- CHU de Bordeaux, Department of Neurology, Bordeaux, France
| | - Guillaume Mathey
- Department of Neurology, Nancy University Hospital, Nancy, France
- Université de Lorraine, Inserm, INSPIIRE, Nancy, France
| | - Pierre-Antoine Gourraud
- Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
- Service de Neurologie, Centre Hospitalier Universitaire (CHU) Nantes, CRC-SEP Pays de la Loire, CIC 1413, Nantes, France
| | - Karin Tarte
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, LabEx IGO, Rennes, France
- Pole Biologie-Centre Hospitalier Universitaire (CHU) Rennes, Rennes, France
| | - Celine Delaloy
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, LabEx IGO, Rennes, France
| | - Patricia Amé
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, LabEx IGO, Rennes, France
- Pole Biologie-Centre Hospitalier Universitaire (CHU) Rennes, Rennes, France
| | - Mikael Roussel
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, LabEx IGO, Rennes, France
- Pole Biologie-Centre Hospitalier Universitaire (CHU) Rennes, Rennes, France
| | - Laure Michel
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, LabEx IGO, Rennes, France
- Pole Biologie-Centre Hospitalier Universitaire (CHU) Rennes, Rennes, France
- Observatoire Français de la Sclérose en Plaques, Centre de Recherche en Neurosciences de Lyon, INSERM 1028 and CNRS UMR 5292, Lyon, France
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Ortega MC, Vila-Del Sol V, Machín-Díaz I, Clemente D. Detection of Monocytic Myeloid-Derived Suppressor Cells in the Human Brain and Blood. Methods Mol Biol 2025; 2899:89-109. [PMID: 40067619 DOI: 10.1007/978-1-0716-4386-0_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2025]
Abstract
The analysis of monocytic myeloid-derived suppressor cells (M-MDSCs) is gaining importance in the complex pathological context of neuroinflammatory diseases. M-MDSCs exert their potent immunoregulatory activity in both the central nervous system and the periphery. Since M-MDSCs lack a specific marker for their identification, the design and development of complex antibody panels for advanced confocal microscopy and flow cytometry techniques are needed to consistently and systematically detect them in both the brain and peripheral blood of human subjects.
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Affiliation(s)
- María Cristina Ortega
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos-SESCAM-IDISCAM, Toledo, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Madrid, Spain
| | - Virginia Vila-Del Sol
- Flow Cytometry Service, Hospital Nacional de Parapléjicos, SESCAM-IDISCAM, Toledo, Spain
| | - Isabel Machín-Díaz
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos-SESCAM-IDISCAM, Toledo, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Madrid, Spain
| | - Diego Clemente
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos-SESCAM-IDISCAM, Toledo, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Madrid, Spain.
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Gogoleva VS, Mundt S, De Feo D, Becher B. Mononuclear phagocytes in autoimmune neuroinflammation. Trends Immunol 2024; 45:814-823. [PMID: 39307582 DOI: 10.1016/j.it.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/23/2024] [Accepted: 08/25/2024] [Indexed: 10/13/2024]
Abstract
A healthy mammalian central nervous system (CNS) harbors a diverse population of leukocytes including members of the mononuclear phagocyte system (MPS). Exerting their specific functions, CNS tissue-resident macrophages as well as associated monocytes and dendritic cells (DCs) maintain CNS homeostasis. Under neuroinflammatory conditions, leukocytes from the systemic immune compartment invade the CNS. This review focuses on the newly discovered roles of the MPS in autoimmune neuroinflammation elicited by encephalitogenic T cells. We propose that CNS-associated DCs act as gatekeepers and antigen-presenting cells that guide the adaptive immune response while bone marrow (BM)-derived monocytes contribute to immunopathology and tissue damage. By contrast, CNS-resident macrophages primarily support tissue function and promote the repair and maintenance of CNS functions.
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Affiliation(s)
- Violetta S Gogoleva
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Sarah Mundt
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Donatella De Feo
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
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Chen Z, Sun H, Zhang W, Hou S, Yang X, Lin J, Ma X, Meng H. Exploring correlations between immune cell phenotypes and the risk of epilepsy: A bidirectional Mendelian randomization study. Epilepsy Behav 2024; 157:109896. [PMID: 38905914 DOI: 10.1016/j.yebeh.2024.109896] [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: 03/04/2024] [Revised: 05/11/2024] [Accepted: 06/09/2024] [Indexed: 06/23/2024]
Abstract
BACKGROUND Neuroinflammation plays an important pathophysiological role in epilepsy; however, the precise connection between immune cells and epilepsy remains unclear. This study used Mendelian randomization (MR) to analyze the causal relationship between 731 immune cell traits and epilepsy. METHODS Based on data from a genome-wide association study (GWAS), a bidirectional two-sample MR analysis was conducted to investigate the potential influence of immune cell phenotypes on epilepsy. Five MR methods were used to analyze the results, with the inverse variance weighted (IVW) method as the primary method, and the results were corrected using the false discovery rate (FDR) method. Sensitivity analyses were performed to test for heterogeneity and horizontal pleiotropy. RESULTS After correction for FDR, four immune traits remained significantly associated with epilepsy risk: CD25 expression on memory (OR = 1.04, 95 % CI = 1.02 ∼ 1.06,P = 2.55 × 10-4), IgD+CD38dim (OR = 1.05, 95 % CI = 1.02 ∼ 1.08, P = 4.73 × 10-4), CD24+CD27+ (OR = 1.04, 95 % CI = 1.02 ∼ 1.06, P = 4.82 × 10-4), and IgD-CD38dim (OR = 1.04, 95 % CI = 1.02 ∼ 1.06, P = 1.04 × 10-3) B cells. The risk of generalized epilepsy was significantly associated with two immune cell traits, whereas that of focal epilepsy was significantly associated with seven immune cell traits. Furthermore, immune cell phenotypes are not affected by genetically predicted epilepsy. CONCLUSION This MR study affirms the causal connection between circulating immune cells and epilepsy, offering guidance for further understanding of the immune mechanisms that underlie epilepsy and the discovery of novel targets for therapy.
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Affiliation(s)
- Zhiqing Chen
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Huaiyu Sun
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Wuqiong Zhang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Shuai Hou
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Xi Yang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Jingqi Lin
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Xiaohui Ma
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Hongmei Meng
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China.
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Nepal MR, Shah S, Kang KT. Dual roles of myeloid-derived suppressor cells in various diseases: a review. Arch Pharm Res 2024; 47:597-616. [PMID: 39008186 DOI: 10.1007/s12272-024-01504-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 06/30/2024] [Indexed: 07/16/2024]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that originate from bone marrow stem cells. In pathological conditions, such as autoimmune disorders, allergies, infections, and cancer, normal myelopoiesis is altered to facilitate the formation of MDSCs. MDSCs were first shown to promote cancer initiation and progression by immunosuppression with the assistance of various chemokines and cytokines. Recently, various studies have demonstrated that MDSCs play two distinct roles depending on the physiological and pathological conditions. MDSCs have protective roles in autoimmune disorders (such as uveoretinitis, multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis, type 1 diabetes, autoimmune hepatitis, inflammatory bowel disease, alopecia areata, and systemic lupus erythematosus), allergies, and organ transplantation. However, they play negative roles in infections and various cancers. Several immunosuppressive functions and mechanisms of MDSCs have been determined in different disease conditions. This review comprehensively discusses the associations between MDSCs and various pathological conditions and briefly describes therapeutic approaches.
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Affiliation(s)
- Mahesh Raj Nepal
- College of Pharmacy, Duksung Women's University, Seoul, South Korea
- Duksung Innovative Drug Center, Duksung Women's University, Seoul, South Korea
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Sajita Shah
- College of Pharmacy, Duksung Women's University, Seoul, South Korea
- Duksung Innovative Drug Center, Duksung Women's University, Seoul, South Korea
- The Comprehensive Cancer Center, Department of Radiation Oncology, Ohio State University, Columbus, OH, USA
| | - Kyu-Tae Kang
- College of Pharmacy, Duksung Women's University, Seoul, South Korea.
- Duksung Innovative Drug Center, Duksung Women's University, Seoul, South Korea.
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Jiang Q, Duan J, Van Kaer L, Yang G. The Role of Myeloid-Derived Suppressor Cells in Multiple Sclerosis and Its Animal Model. Aging Dis 2024; 15:1329-1343. [PMID: 37307825 PMCID: PMC11081146 DOI: 10.14336/ad.2023.0323-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 03/23/2023] [Indexed: 06/14/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs), a heterogeneous cell population that consists of mostly immature myeloid cells, are immunoregulatory cells mainly characterized by their suppressive functions. Emerging findings have revealed the involvement of MDSCs in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). MS is an autoimmune and degenerative disease of the central nervous system characterized by demyelination, axon loss, and inflammation. Studies have reported accumulation of MDSCs in inflamed tissues and lymphoid organs of MS patients and EAE mice, and these cells display dual functions in EAE. However, the contribution of MDSCs to MS/EAE pathogenesis remains unclear. This review aims to summarize our current understanding of MDSC subsets and their possible roles in MS/EAE pathogenesis. We also discuss the potential utility and associated obstacles in employing MDSCs as biomarkers and cell-based therapies for MS.
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Affiliation(s)
- Qianling Jiang
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong, China.
| | - Jielin Duan
- Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Luc Van Kaer
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
| | - Guan Yang
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong, China.
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9
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Camacho-Toledano C, Machín-Díaz I, Lebrón-Galán R, González-Mayorga A, Palomares FJ, Serrano MC, Clemente D. Graphene oxide films as a novel tool for the modulation of myeloid-derived suppressor cell activity in the context of multiple sclerosis. NANOSCALE 2024; 16:7515-7531. [PMID: 38498071 DOI: 10.1039/d3nr05351b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Despite the pharmacological arsenal approved for Multiple Sclerosis (MS), there are treatment-reluctant patients for whom cell therapy appears as the only therapeutic alternative. Myeloid-derived suppressor cells (MDSCs) are immature cells of the innate immunity able to control the immune response and to promote oligodendroglial differentiation in the MS animal model experimental autoimmune encephalomyelitis (EAE). However, when isolated and cultured for cell therapy purposes, MDSCs lose their beneficial immunomodulatory properties. To prevent this important drawback, culture devices need to be designed so that MDSCs maintain a state of immaturity and immunosuppressive function similar to that exerted in the donor organism. With this aim, we select graphene oxide (GO) as a promising candidate as it has been described as a biocompatible nanomaterial with the capacity to biologically modulate different cell types, yet its immunoactive potential has been poorly explored to date. In this work, we have fabricated GO films with two distintive redox and roughness properties and explore their impact in MDSC culture right after isolation. Our results show that MDSCs isolated from immune organs of EAE mice maintain an immature phenotype and highly immunosuppressive activity on T lymphocytes after being cultured on highly-reduced GO films (rGO200) compared to those grown on conventional glass coverslips. This immunomodulation effect is depleted when MDSCs are exposed to slightly rougher and more oxidized GO substrates (rGO90), in which cells experience a significant reduction in cell size associated with the activation of apoptosis. Taken together, the exposure of MDSCs to GO substrates with different redox state and roughness is presented as a good strategy to control MDSC activity in vitro. The versatility of GO nanomaterials in regards to the impact of their physico-chemical properties in immunomodulation opens the door to their selective therapeutic potential for pathologies where MDSCs need to be enhanced (MS) or inhibited (cancer).
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Affiliation(s)
- Celia Camacho-Toledano
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos (HNP), SESCAM, Finca La Peraleda s/n, 45071-Toledo, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Av. Monforte de Lemos, 3-5, 28029-Madrid, Spain
| | - Isabel Machín-Díaz
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos (HNP), SESCAM, Finca La Peraleda s/n, 45071-Toledo, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Av. Monforte de Lemos, 3-5, 28029-Madrid, Spain
| | - Rafael Lebrón-Galán
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos (HNP), SESCAM, Finca La Peraleda s/n, 45071-Toledo, Spain.
| | - Ankor González-Mayorga
- Laboratory of Interfaces for Neural Repair, Hospital Nacional de Parapléjicos, SESCAM, Finca La Peraleda s/n, 45071- Toledo, Spain
| | - Francisco J Palomares
- Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Calle Sor Juana Inés de la Cruz 3, 28049-Madrid, Spain.
| | - María C Serrano
- Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas (CSIC), Calle Sor Juana Inés de la Cruz 3, 28049-Madrid, Spain.
| | - Diego Clemente
- Neuroimmune-Repair Group, Hospital Nacional de Parapléjicos (HNP), SESCAM, Finca La Peraleda s/n, 45071-Toledo, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Av. Monforte de Lemos, 3-5, 28029-Madrid, Spain
- Design and development of biomaterials for neural regeneration, HNP, Associated Unit to CSIC through ICMM, Finca La Peraleda s/n, 45071-Toledo, Spain
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10
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Tamberi L, Belloni A, Pugnaloni A, Rippo MR, Olivieri F, Procopio AD, Bronte G. The Influence of Myeloid-Derived Suppressor Cell Expansion in Neuroinflammation and Neurodegenerative Diseases. Cells 2024; 13:643. [PMID: 38607083 PMCID: PMC11011419 DOI: 10.3390/cells13070643] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/03/2024] [Accepted: 04/05/2024] [Indexed: 04/13/2024] Open
Abstract
The neuro-immune axis has a crucial function both during physiological and pathological conditions. Among the immune cells, myeloid-derived suppressor cells (MDSCs) exert a pivotal role in regulating the immune response in many pathological conditions, influencing neuroinflammation and neurodegenerative disease progression. In chronic neuroinflammation, MDSCs could lead to exacerbation of the inflammatory state and eventually participate in the impairment of cognitive functions. To have a complete overview of the role of MDSCs in neurodegenerative diseases, research on PubMed for articles using a combination of terms made with Boolean operators was performed. According to the search strategy, 80 papers were retrieved. Among these, 44 papers met the eligibility criteria. The two subtypes of MDSCs, monocytic and polymorphonuclear MDSCs, behave differently in these diseases. The initial MDSC proliferation is fundamental for attenuating inflammation in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), but not in amyotrophic lateral sclerosis (ALS), where MDSC expansion leads to exacerbation of the disease. Moreover, the accumulation of MDSC subtypes in distinct organs changes during the disease. The proliferation of MDSC subtypes occurs at different disease stages and can influence the progression of each neurodegenerative disorder differently.
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Affiliation(s)
- Lorenza Tamberi
- Department of Clinical and Molecular Sciences (DISCLIMO), Polytechnic University of Marche, 60121 Ancona, Italy; (L.T.); (A.P.); (M.R.R.); (F.O.); (A.D.P.); (G.B.)
| | - Alessia Belloni
- Department of Clinical and Molecular Sciences (DISCLIMO), Polytechnic University of Marche, 60121 Ancona, Italy; (L.T.); (A.P.); (M.R.R.); (F.O.); (A.D.P.); (G.B.)
| | - Armanda Pugnaloni
- Department of Clinical and Molecular Sciences (DISCLIMO), Polytechnic University of Marche, 60121 Ancona, Italy; (L.T.); (A.P.); (M.R.R.); (F.O.); (A.D.P.); (G.B.)
| | - Maria Rita Rippo
- Department of Clinical and Molecular Sciences (DISCLIMO), Polytechnic University of Marche, 60121 Ancona, Italy; (L.T.); (A.P.); (M.R.R.); (F.O.); (A.D.P.); (G.B.)
| | - Fabiola Olivieri
- Department of Clinical and Molecular Sciences (DISCLIMO), Polytechnic University of Marche, 60121 Ancona, Italy; (L.T.); (A.P.); (M.R.R.); (F.O.); (A.D.P.); (G.B.)
- Clinic of Laboratory and Precision Medicine, National Institute of Health and Sciences on Ageing (IRCCS INRCA), 60124 Ancona, Italy
| | - Antonio Domenico Procopio
- Department of Clinical and Molecular Sciences (DISCLIMO), Polytechnic University of Marche, 60121 Ancona, Italy; (L.T.); (A.P.); (M.R.R.); (F.O.); (A.D.P.); (G.B.)
- Clinic of Laboratory and Precision Medicine, National Institute of Health and Sciences on Ageing (IRCCS INRCA), 60124 Ancona, Italy
| | - Giuseppe Bronte
- Department of Clinical and Molecular Sciences (DISCLIMO), Polytechnic University of Marche, 60121 Ancona, Italy; (L.T.); (A.P.); (M.R.R.); (F.O.); (A.D.P.); (G.B.)
- Clinic of Laboratory and Precision Medicine, National Institute of Health and Sciences on Ageing (IRCCS INRCA), 60124 Ancona, Italy
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11
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Del Pilar C, Garrido-Matilla L, Del Pozo-Filíu L, Lebrón-Galán R, Arias RF, Clemente D, Alonso JR, Weruaga E, Díaz D. Intracerebellar injection of monocytic immature myeloid cells prevents the adverse effects caused by stereotactic surgery in a model of cerebellar neurodegeneration. J Neuroinflammation 2024; 21:49. [PMID: 38355633 PMCID: PMC10867997 DOI: 10.1186/s12974-023-03000-8] [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: 09/14/2023] [Accepted: 12/18/2023] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) constitute a recently discovered bone-marrow-derived cell type useful for dealing with neuroinflammatory disorders. However, these cells are only formed during inflammatory conditions from immature myeloid cells (IMCs) that acquire immunosuppressive activity, thus being commonly gathered from diseased animals. Then, to obtain a more clinically feasible source, we characterized IMCs directly derived from healthy bone marrow and proved their potential immunosuppressive activity under pathological conditions in vitro. We then explored their neuroprotective potential in a model of human cerebellar ataxia, the Purkinje Cell Degeneration (PCD) mouse, as it displays a well-defined neurodegenerative and neuroinflammatory process that can be also aggravated by invasive surgeries. METHODS IMCs were obtained from healthy bone marrow and co-cultured with activated T cells. The proliferation and apoptotic rate of the later were analyzed with Tag-it Violet. For in vivo studies, IMCs were transplanted by stereotactic surgery into the cerebellum of PCD mice. We also used sham-operated animals as controls of the surgical effects, as well as their untreated counterparts. Motor behavior of mice was assessed by rotarod test. The Purkinje cell density was measured by immunohistochemistry and cell death assessed with the TUNEL technique. We also analyzed the microglial phenotype by immunofluorescence and the expression pattern of inflammation-related genes by qPCR. Parametric tests were applied depending on the specific experiment: one or two way ANOVA and Student's T test. RESULTS IMCs were proven to effectively acquire immunosuppressive activity under pathological conditions in vitro, thus acting as MDSCs. Concerning in vivo studios, sham-operated PCD mice suffered detrimental effects in motor coordination, Purkinje cell survival and microglial activation. After intracranial administration of IMCs into the cerebellum of PCD mice, no special benefits were detected in the transplanted animals when compared to untreated mice. Nonetheless, this transplant almost completely prevented the impairments caused by the surgery in PCD mice, probably by the modulation of the inflammatory patterns. CONCLUSIONS Our work comprise two main translational findings: (1) IMCs can be directly used as they behave as MDSCs under pathological conditions, thus avoiding their gathering from diseased subjects; (2) IMCs are promising adjuvants when performing neurosurgery.
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Affiliation(s)
- Carlos Del Pilar
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain
| | - Lucía Garrido-Matilla
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Departamento de Psicobiología, Facultad de Psicología, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
| | - Lucía Del Pozo-Filíu
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Translational Stroke Laboratory (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Rafael Lebrón-Galán
- Neuroimmuno-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45004, Toledo, Spain
- Hospital Universitario de Toledo, Avd. Río Guadiana, s/n, 45007, Toledo, Spain
| | - Raúl F Arias
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain
| | - Diego Clemente
- Neuroimmuno-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45004, Toledo, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Av. Monforte de Lemos, 3-5, 28029, Madrid, Spain
| | - José Ramón Alonso
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain
| | - Eduardo Weruaga
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain.
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain.
| | - David Díaz
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain.
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain.
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12
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Chen L, Zhu LF, Zhang LY, Chu YH, Dong MH, Pang XW, Yang S, Zhou LQ, Shang K, Xiao J, Wang W, Qin C, Tian DS. Causal association between the peripheral immunity and the risk and disease severity of multiple sclerosis. Front Immunol 2024; 15:1325938. [PMID: 38390334 PMCID: PMC10881847 DOI: 10.3389/fimmu.2024.1325938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 01/25/2024] [Indexed: 02/24/2024] Open
Abstract
Background Growing evidence links immunological responses to Multiple sclerosis (MS), but specific immune factors are still unclear. Methods Mendelian randomization (MR) was performed to investigate the association between peripheral hematological traits, MS risk, and its severity. Then, further subgroup analysis of immune counts and circulating cytokines and growth factors were performed. Results MR revealed higher white blood cell count (OR [95%CI] = 1.26 [1.10,1.44], P = 1.12E-03, P adjust = 3.35E-03) and lymphocyte count (OR [95%CI] = 1.31 [1.15,1.50], P = 5.37E-05, P adjust = 3.22E-04) increased the risk of MS. In further analysis, higher T cell absolute count (OR [95%CI] = 2.04 [1.36,3.08], P = 6.37E-04, P adjust = 2.19E-02) and CD4+ T cell absolute count (OR [95%CI] = 2.11 [1.37,3.24], P = 6.37E-04, P adjust = 2.19E-02), could increase MS risk. While increasing CD25++CD4+ T cell absolute count (OR [95%CI] = 0.75 [0.66,0.86], P = 2.12E-05, P adjust = 1.72E-03), CD25++CD4+ T cell in T cell (OR [95%CI] = 0.79[0.70,0.89], P = 8.54E-05, P adjust = 5.29E-03), CD25++CD4+ T cell in CD4+ T cell (OR [95%CI] = 0.80[0.72,0.89], P = 1.85E-05, P adjust = 1.72E-03), and CD25++CD8+ T cell in T cell (OR [95%CI] = 0.68[0.57,0.81], P = 2.22E-05, P adjust = 1.72E-03), were proved to be causally defensive for MS. For the disease severity, the suggestive association between some traits related to CD4+ T cell, Tregs and MS severity were demonstrated. Moreover, elevated levels of IL-2Ra had a detrimental effect on the risk of MS (OR [95%CI] = 1.22 [1.12,1.32], P = 3.20E-06, P adjust = 1.34E-04). Conclusions This study demonstrated a genetically predicted causal relationship between elevated peripheral immune cell counts and MS. Subgroup analysis revealed a specific contribution of peripheral immune cells, holding potential for further investigations into the underlying mechanisms of MS and its severity.
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Affiliation(s)
- Lian Chen
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Li-Fang Zhu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Lu-Yang Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Yun-Hui Chu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Ming-Hao Dong
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-Wei Pang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Sheng Yang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Luo-Qi Zhou
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Ke Shang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Xiao
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Wang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Chuan Qin
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Dai-Shi Tian
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
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13
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Xiong X, Zhang Y, Wen Y. Diverse functions of myeloid-derived suppressor cells in autoimmune diseases. Immunol Res 2024; 72:34-49. [PMID: 37733169 PMCID: PMC10811123 DOI: 10.1007/s12026-023-09421-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 08/31/2023] [Indexed: 09/22/2023]
Abstract
Since myeloid-derived suppressor cells (MDSCs) were found suppressing immune responses in cancer and other pathological conditions, subsequent researchers have pinned their hopes on the suppressive function against immune damage in autoimmune diseases. However, recent studies have found key distinctions of MDSC immune effects in cancer and autoimmunity. These include not only suppression and immune tolerance, but MDSCs also possess pro-inflammatory effects and exacerbate immune disorders during autoimmunity, while promoting T cell proliferation, inducing Th17 cell differentiation, releasing pro-inflammatory cytokines, and causing direct tissue damage. Additionally, MDSCs could interact with surrounding cells to directly cause tissue damage or repair, sometimes even as an inflammatory indicator in line with disease severity. These diverse manifestations could be partially attributed to the heterogeneity of MDSCs, but not all. The different disease types, disease states, and cytokine profiles alter the diverse phenotypes and functions of MDSCs, thus leading to the impairment or obversion of MDSC suppression. In this review, we summarize the functions of MDSCs in several autoimmune diseases and attempt to elucidate the mechanisms behind their actions.
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Affiliation(s)
- Xin Xiong
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Zhang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Wen
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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14
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Zanghì A, Di Filippo PS, Avolio C, D’Amico E. Myeloid-derived Suppressor Cells and Multiple Sclerosis. Curr Neuropharmacol 2024; 23:36-57. [PMID: 38988152 PMCID: PMC11519824 DOI: 10.2174/1570159x22999240710142942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 02/17/2024] [Accepted: 02/23/2024] [Indexed: 07/12/2024] Open
Abstract
Myeloid-Derived Suppressor Cells (MDSCs) are a heterogeneous population of immature myeloid cells that play important roles in maintaining immune homeostasis and regulating immune responses. MDSCs can be divided into two main subsets based on their surface markers and functional properties: granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs). Recently greatest attention has been paid to innate immunity in Multiple Sclerosis (MS), so the aim of our review is to provide an overview of the main characteristics of MDSCs in MS and its preclinical model by discussing the most recent data available. The immunosuppressive functions of MDSCs can be dysregulated in MS, leading to an exacerbation of the autoimmune response and disease progression. Antigen-specific peptide immunotherapy, which aims to restore tolerance while avoiding the use of non-specific immunosuppressive drugs, is a promising approach for autoimmune diseases, but the cellular mechanisms behind successful therapy remain poorly understood. Therefore, targeting MDSCs could be a promising therapeutic approach for MS. Various strategies for modulating MDSCs have been investigated, including the use of pharmacological agents, biological agents, and adoptive transfer of exogenous MDSCs. However, it remained unclear whether MDSCs display any therapeutic potential in MS and how this therapy could modulate different aspects of the disease. Collectively, all the described studies revealed a pivotal role for MDSCs in the regulation of MS.
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Affiliation(s)
- Aurora Zanghì
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | | | - Carlo Avolio
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Emanuele D’Amico
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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15
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Benítez‐Fernández R, Josa‐Prado F, Sánchez E, Lao Y, García‐Rubia A, Cumella J, Martínez A, Palomo V, de Castro F. Efficacy of a benzothiazole-based LRRK2 inhibitor in oligodendrocyte precursor cells and in a murine model of multiple sclerosis. CNS Neurosci Ther 2024; 30:e14552. [PMID: 38287523 PMCID: PMC10808848 DOI: 10.1111/cns.14552] [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: 02/13/2023] [Revised: 10/30/2023] [Accepted: 11/09/2023] [Indexed: 01/31/2024] Open
Abstract
AIMS Multiple sclerosis (MS) is a chronic neurological disease that currently lacks effective curative treatments. There is a need to find effective therapies, especially to reverse the progressive demyelination and neuronal damage. Oligodendrocytes form the myelin sheath around axons in the central nervous system (CNS) and oligodendrocyte precursor cells (OPCs) undergo mechanisms that enable spontaneously the partial repair of damaged lesions. The aim of this study was to discover small molecules with potential effects in demyelinating diseases, including (re)myelinating properties. METHODS Recently, it has been shown how LRRK2 inhibition promotes oligodendrogliogenesis and therefore an efficient repair or myelin damaged lesions. Here we explored small molecules inhibiting LRRK2 as potential enhancers of primary OPCs proliferation and differentiation, and their potential impact on the clinical score of experimental autoimmune encephalomyelitys (EAE) mice, a validated model of the most frequent clinical form of MS, relapsing-remitting MS. RESULTS One of the LRRK2 inhibitors presented in this study promoted the proliferation and differentiation of OPC primary cultures. When tested in the EAE murine model of MS, it exerted a statistically significant reduction of the clinical burden of the animals, and histological evidence revealed how the treated animals presented a reduced lesion area in the spinal cord. CONCLUSIONS For the first time, a small molecule with LRRK2 inhibition properties presented (re)myelinating properties in primary OPCs cultures and potentially in the in vivo murine model. This study provides an in vivo proof of concept for a LRRK2 inhibitor, confirming its potential for the treatment of MS.
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Affiliation(s)
- Rocío Benítez‐Fernández
- Centro de Investigaciones Biológicas Margarita Salas‐CSICMadridSpain
- Instituto Cajal‐CSICMadridSpain
| | | | | | | | | | - José Cumella
- Instituto de Química Médica, IQM‐CSICMadridSpain
| | - Ana Martínez
- Centro de Investigaciones Biológicas Margarita Salas‐CSICMadridSpain
- Centro de Investigaciones Biomédicas en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos IIIMadridSpain
| | - Valle Palomo
- Centro de Investigaciones Biomédicas en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos IIIMadridSpain
- Instituto Madrileño de Estudios AvanzadosIMDEA NanocienciaMadridSpain
- Unidad de Nanobiotecnología Asociada al Centro Nacional de Biotecnología (CNB‐CSIC)MadridSpain
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16
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Bekić M, Tomić S. Myeloid-derived suppressor cells in the therapy of autoimmune diseases. Eur J Immunol 2023; 53:e2250345. [PMID: 37748117 DOI: 10.1002/eji.202250345] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 08/14/2023] [Accepted: 09/20/2023] [Indexed: 09/27/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are well recognized as critical factors in the pathology of tumors. However, their roles in autoimmune diseases are still unclear, which hampers the development of efficient immunotherapies. The role of different MDSCs subsets in multiple sclerosis, inflammatory bowel diseases, rheumatoid arthritis, type 1 diabetes, and systemic lupus erythematosus displayed different mechanisms of immune suppression, and several studies pointed to MDSCs' capacity to induce T-helper (Th)17 cells and tissue damage. These results also suggested that MDSCs could be present in different functional states and utilize different mechanisms for controlling the activity of T and B cells. Therefore, various therapeutic strategies should be employed to restore homeostasis in autoimmune diseases. The therapies harnessing MDSCs could be designed either as cell therapy or rely on the expansion and activation of MDSCs in vivo, or their depletion. Cumulatively, MDSCs are inevitable players in autoimmunity, and rational approaches in developing therapies are required to avoid the adverse effects of MDSCs and harness their suppressive mechanisms to improve the overall efficacy of autoimmunity therapy.
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Affiliation(s)
- Marina Bekić
- Institute for the Application of Nuclear Energy, University in Belgrade, Beograd, Serbia
| | - Sergej Tomić
- Institute for the Application of Nuclear Energy, University in Belgrade, Beograd, Serbia
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17
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Iglesias-Escudero M, San Segundo D, López-Hoyos M. CD4+ T cells proliferation assay to analyze Mo-MDSCs suppressive function. Methods Cell Biol 2023; 184:69-84. [PMID: 38555159 DOI: 10.1016/bs.mcb.2023.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
Among myeloid regulatory cells (MRCs), some particular subsets termed myeloid-derived suppressor cells (MDSCs) have been described. They are suppressor myeloid cells characterized by their ability to regulate innate and adaptive immune responses and known to accumulate in the context of chronic diseases and cancer. The lack of specific markers makes their classification difficult and requires functional studies to distinguish them from other myeloid cells. In this sense, the in vitro analysis of the proliferation of T lymphocytes cultured with MDSCs provides information about the regulatory function of these cells. Here, we provide a detailed protocol to assess the ability of human Mo-MDSCs to suppress T cell proliferation in vitro after obtaining Mo-MDSCs and CD4+T cell from peripheral blood.
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Affiliation(s)
| | - David San Segundo
- Transplant and Autoimmunity Group, Research Institute-IDIVAL, Santander, Spain; Universitary Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain
| | - Marcos López-Hoyos
- Transplant and Autoimmunity Group, Research Institute-IDIVAL, Santander, Spain; Universitary Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain; Molecular Biology Department, University of Cantabria, Santander, Spain.
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18
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Ortega MC, Lebrón-Galán R, Machín-Díaz I, Naughton M, Pérez-Molina I, García-Arocha J, Garcia-Dominguez JM, Goicoechea-Briceño H, Vila-Del Sol V, Quintanero-Casero V, García-Montero R, Galán V, Calahorra L, Camacho-Toledano C, Martínez-Ginés ML, Fitzgerald DC, Clemente D. Central and peripheral myeloid-derived suppressor cell-like cells are closely related to the clinical severity of multiple sclerosis. Acta Neuropathol 2023; 146:263-282. [PMID: 37243699 PMCID: PMC10329064 DOI: 10.1007/s00401-023-02593-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 05/10/2023] [Accepted: 05/21/2023] [Indexed: 05/29/2023]
Abstract
Multiple sclerosis (MS) is a highly heterogeneous demyelinating disease of the central nervous system (CNS) that needs for reliable biomarkers to foresee disease severity. Recently, myeloid-derived suppressor cells (MDSCs) have emerged as an immune cell population with an important role in MS. The monocytic-MDSCs (M-MDSCs) share the phenotype with Ly-6Chi-cells in the MS animal model, experimental autoimmune encephalomyelitis (EAE), and have been retrospectively related to the severity of the clinical course in the EAE. However, no data are available about the presence of M-MDSCs in the CNS of MS patients or its relation with the future disease aggressiveness. In this work, we show for the first time cells exhibiting all the bona-fide phenotypical markers of M-MDSCs associated with MS lesions, whose abundance in these areas appears to be directly correlated with longer disease duration in primary progressive MS patients. Moreover, we show that blood immunosuppressive Ly-6Chi-cells are strongly related to the future severity of EAE disease course. We found that a higher abundance of Ly-6Chi-cells at the onset of the EAE clinical course is associated with a milder disease course and less tissue damage. In parallel, we determined that the abundance of M-MDSCs in blood samples from untreated MS patients at their first relapse is inversely correlated with the Expanded Disability Status Scale (EDSS) at baseline and after a 1-year follow-up. In summary, our data point to M-MDSC load as a factor to be considered for future studies focused on the prediction of disease severity in EAE and MS.
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Affiliation(s)
- María Cristina Ortega
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, SESCAM, Finca "La Peraleda" s/n, 45071, Toledo, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, c/Monforte de Lemos, 3-5, 28029, Madrid, Spain
| | - Rafael Lebrón-Galán
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, SESCAM, Finca "La Peraleda" s/n, 45071, Toledo, Spain
| | - Isabel Machín-Díaz
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, SESCAM, Finca "La Peraleda" s/n, 45071, Toledo, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, c/Monforte de Lemos, 3-5, 28029, Madrid, Spain
| | - Michelle Naughton
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Rd, Belfast, BT9 7BL, Northern Ireland, UK
| | - Inmaculada Pérez-Molina
- Departamento de Neurología, Hospital Universitario de Toledo, Av. del Río Guadiana, 45007, Toledo, Spain
| | - Jennifer García-Arocha
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, SESCAM, Finca "La Peraleda" s/n, 45071, Toledo, Spain
| | - Jose Manuel Garcia-Dominguez
- Departamento de Neurología, Hospital General Universitario Gregorio Marañón, Calle del Dr. Esquerdo 46, 28007, Madrid, Spain
| | - Haydee Goicoechea-Briceño
- Departamento de Neurología, Hospital General Universitario Gregorio Marañón, Calle del Dr. Esquerdo 46, 28007, Madrid, Spain
| | - Virginia Vila-Del Sol
- Servicio de Citometría de Flujo, Hospital Nacional de Parapléjicos, SESCAM, Finca "La Peraleda" s/n, 45071, Toledo, Spain
| | - Víctor Quintanero-Casero
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, SESCAM, Finca "La Peraleda" s/n, 45071, Toledo, Spain
| | - Rosa García-Montero
- Departamento de Neurología, Hospital Universitario de Toledo, Av. del Río Guadiana, 45007, Toledo, Spain
| | - Victoria Galán
- Departamento de Neurología, Hospital Universitario de Toledo, Av. del Río Guadiana, 45007, Toledo, Spain
| | - Leticia Calahorra
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, SESCAM, Finca "La Peraleda" s/n, 45071, Toledo, Spain
| | - Celia Camacho-Toledano
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, SESCAM, Finca "La Peraleda" s/n, 45071, Toledo, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, c/Monforte de Lemos, 3-5, 28029, Madrid, Spain
| | - María Luisa Martínez-Ginés
- Departamento de Neurología, Hospital General Universitario Gregorio Marañón, Calle del Dr. Esquerdo 46, 28007, Madrid, Spain
| | - Denise C Fitzgerald
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Rd, Belfast, BT9 7BL, Northern Ireland, UK
| | - Diego Clemente
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, SESCAM, Finca "La Peraleda" s/n, 45071, Toledo, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, c/Monforte de Lemos, 3-5, 28029, Madrid, Spain.
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19
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Xiong X, Yu M, Wang D, Wang Y, Cheng L. Th17/Treg balance is regulated by myeloid-derived suppressor cells in experimental autoimmune myocarditis. Immun Inflamm Dis 2023; 11:e872. [PMID: 37382257 PMCID: PMC10266145 DOI: 10.1002/iid3.872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 04/24/2023] [Accepted: 04/27/2023] [Indexed: 06/30/2023] Open
Abstract
OBJECTIVE Autoimmune myocarditis is caused by both innate and adaptive immune responses. Many studies have found that myeloid-derived suppressor cells (MDSCs) suppress T-cell responses and reduce immune tolerance, while MDSCs may serve as a key player in inflammatory responses and pathogenesis in variety of autoimmune diseases. However, research into the role of MDSCs in experimental autoimmune myocarditis (EAM) remains lacking. METHODS AND RESULTS We discovered that the expansion of MDSCs in EAM was closely related to the severity of myocardial inflammation. At an early stage of EAM, both adoptive transfer (AT) and selective depletion of MDSCs could inhibit the expression of IL-17 in CD4+ cells and downregulate the Th17/Treg ratio, alleviating excessive inflammation of EAM myocarditis. In another experiment, in addition, MDSCs transferred after selective depletion could increase IL-17 and Foxp3 expressions in CD4+ cells, as well as the Th17/Treg ratio, contributing to the aggravation of myocardial inflammation. MDSCs promoted the Th17 cell induction under Th17-polarizing conditions in vitro but suppressed Treg expansion. CONCLUSION These findings suggest that MDSCs play a plastic role in sustaining mild inflammation in EAM by shifting Th17/Treg balance.
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Affiliation(s)
- Xin Xiong
- Department of Pediatrics, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Mengjia Yu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Dinghang Wang
- Department of Emergency, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yange Wang
- Department of Cardiologythe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Longxian Cheng
- Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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20
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Rui K, Peng N, Xiao F, Lu L, Tian J. New insights into the functions of MDSCs in autoimmune pathogenesis. Cell Mol Immunol 2023; 20:548-550. [PMID: 37012396 PMCID: PMC10203147 DOI: 10.1038/s41423-023-01004-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 03/11/2023] [Indexed: 04/05/2023] Open
Affiliation(s)
- Ke Rui
- Institute of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Na Peng
- Department of Rheumatology, the Second People's Hospital, China Three Gorges University, Yichang, China
| | - Fan Xiao
- Department of Pathology and HKU-Shenzhen Hospital, The University of Hong Kong, Hong Kong, China
- Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong, China
| | - Liwei Lu
- Department of Pathology and HKU-Shenzhen Hospital, The University of Hong Kong, Hong Kong, China.
- Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong, China.
| | - Jie Tian
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
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21
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Műzes G, Sipos F. Autoimmunity and Carcinogenesis: Their Relationship under the Umbrella of Autophagy. Biomedicines 2023; 11:1130. [PMID: 37189748 PMCID: PMC10135912 DOI: 10.3390/biomedicines11041130] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/04/2023] [Accepted: 04/06/2023] [Indexed: 04/11/2023] Open
Abstract
The immune system and autophagy share a functional relationship. Both innate and adaptive immune responses involve autophagy and, depending on the disease's origin and pathophysiology, it may have a detrimental or positive role on autoimmune disorders. As a "double-edged sword" in tumors, autophagy can either facilitate or impede tumor growth. The autophagy regulatory network that influences tumor progression and treatment resistance is dependent on cell and tissue types and tumor stages. The connection between autoimmunity and carcinogenesis has not been sufficiently explored in past studies. As a crucial mechanism between the two phenomena, autophagy may play a substantial role, though the specifics remain unclear. Several autophagy modifiers have demonstrated beneficial effects in models of autoimmune disease, emphasizing their therapeutic potential as treatments for autoimmune disorders. The function of autophagy in the tumor microenvironment and immune cells is the subject of intensive study. The objective of this review is to investigate the role of autophagy in the simultaneous genesis of autoimmunity and malignancy, shedding light on both sides of the issue. We believe our work will assist in the organization of current understanding in the field and promote additional research on this urgent and crucial topic.
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Affiliation(s)
| | - Ferenc Sipos
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary;
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22
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Diagnostic and prognostic value of the RUNXOR/RUNX1 axis in multiple sclerosis. Neurobiol Dis 2023; 178:106032. [PMID: 36754216 DOI: 10.1016/j.nbd.2023.106032] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/08/2023] Open
Abstract
The runt-related transcription factor-1 (RUNX1) gene with its lncRNA RUNXOR are recently becoming a research focus in various diseases, specifically immune-related diseases as they are implicated in multiple pathways. Interestingly, their role in multiple sclerosis (MS) remains unstudied. The present study explored the role of RUNXOR/RUNX1 in the development and progression of MS and investigated their possible mechanism of action. We measured the serum expression levels of lncRNA RUNXOR, as well as RUNX1, microtubule associated protein 2 (MAP2), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) mRNAs in 30 healthy controls and 120 MS patients subdivided into 4 groups: 30 clinically isolated syndrome patients, 30 relapsing-remitting MS (RRMS) patients in relapse, 30 RRMS patients in remission and 30 secondary progressive MS patients. Additionally, we measured the serum protein levels of RUNX1, MAP2, NGF, BDNF and interleukin-10 (IL-10). All measured RNA expression levels were markedly downregulated and, consequently, the protein levels of RUNX1, MAP2, NGF, BDNF and IL-10 were significantly decreased in MS patients compared to healthy controls. Moreover, the levels of the measured parameters varied significantly within the MS groups. According to receiver-operating-characteristic (ROC) curve and logistic regression analyses, lncRNA RUNXOR, RUNX1 mRNA and its protein levels were predictors of disease progression, in addition to RUNX1 mRNA exhibiting a diagnostic potential. Altogether, this study suggests the implication of the RUNXOR-RUNX1 axis in MS development, progression, and increased MS-related disability, and highlights the potential utility of the studied parameters as promising diagnostic/prognostic biomarkers for MS.
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23
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Benítez-Fernández R, Gil C, Guaza C, Mestre L, Martínez A. The Dual PDE7-GSK3β Inhibitor, VP3.15, as Neuroprotective Disease-Modifying Treatment in a Model of Primary Progressive Multiple Sclerosis. Int J Mol Sci 2022; 23:ijms232214378. [PMID: 36430856 PMCID: PMC9694690 DOI: 10.3390/ijms232214378] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/08/2022] [Accepted: 11/17/2022] [Indexed: 11/22/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune and degenerative disease with axonal damage and demyelination as its main features. Its dual neurological and autoimmune nature makes it a disease that is difficult to treat. Treatments that simultaneously stop the immune response while protecting and repairing the nervous system are urgent. That is of utmost importance for the primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS, characterized by worsening neurological function from the onset of symptoms. In this sense, inhibitors of glycogen synthase kinase 3β (GSK3β) and phosphodiesterase 7 (PDE7) have recently shown great therapeutic potential for the treatment of demyelinating diseases. Here we investigated a dual inhibitor of these two targets, the small molecule VP3.15, in a preclinical model, which resembles primary-progressive MS (PPMS), the Theiler's mouse encephalomyelitis virus-induced demyelinated disease (TMEV-IDD). In our study, VP3.15 ameliorates the disease course improving motor deficits of infected mice. Chronic treatment with VP3.15 also showed significant efficacy in the immunomodulation process, as well as in the proliferation and differentiation of oligodendroglial precursors, improving the preservation of myelin and axonal integrity. Therefore, our results support a treatment with the safe VP3.15 as an integrative therapeutic strategy for the treatment of PPMS.
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Affiliation(s)
- Rocio Benítez-Fernández
- Centro de Investigaciones Biológicas Margarita Salas-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
- Instituto Cajal-CSIC, Doctor Arce 37, 28002 Madrid, Spain
| | - Carmen Gil
- Centro de Investigaciones Biológicas Margarita Salas-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Carmen Guaza
- Instituto Cajal-CSIC, Doctor Arce 37, 28002 Madrid, Spain
| | - Leyre Mestre
- Instituto Cajal-CSIC, Doctor Arce 37, 28002 Madrid, Spain
- Correspondence: (L.M.); (A.M.); Tel.: +34-918-703-112 (A.M.)
| | - Ana Martínez
- Centro de Investigaciones Biológicas Margarita Salas-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029Madrid, Spain
- Correspondence: (L.M.); (A.M.); Tel.: +34-918-703-112 (A.M.)
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24
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Camacho-Toledano C, Machín-Díaz I, Calahorra L, Cabañas-Cotillas M, Otaegui D, Castillo-Triviño T, Villar LM, Costa-Frossard L, Comabella M, Midaglia L, García-Domínguez JM, García-Arocha J, Ortega MC, Clemente D. Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis. J Neuroinflammation 2022; 19:277. [PMCID: PMC9675277 DOI: 10.1186/s12974-022-02635-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/30/2022] [Indexed: 11/21/2022] Open
Abstract
Background The increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients. Methods Treatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patients’ peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed. Results Fingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment. Conclusion Our data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02635-3.
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Affiliation(s)
- Celia Camacho-Toledano
- grid.414883.20000 0004 1767 1847Neuroimmuno-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - Isabel Machín-Díaz
- grid.414883.20000 0004 1767 1847Neuroimmuno-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - Leticia Calahorra
- grid.414883.20000 0004 1767 1847Neuroimmuno-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - María Cabañas-Cotillas
- grid.414883.20000 0004 1767 1847Neuroimmuno-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - David Otaegui
- grid.432380.eMultiple Sclerosis Unit, Biodonostia Health Institute, 20014 Donostia-San Sebastián, Spain
| | - Tamara Castillo-Triviño
- grid.432380.eMultiple Sclerosis Unit, Biodonostia Health Institute, 20014 Donostia-San Sebastián, Spain ,grid.414651.30000 0000 9920 5292Neurology Department, Hospital Universitario Donostia, San Sebastián, Spain
| | - Luisa María Villar
- grid.411347.40000 0000 9248 5770Immunology Department, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Lucienne Costa-Frossard
- grid.411347.40000 0000 9248 5770Immunology Department, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain ,grid.411347.40000 0000 9248 5770Multiple Sclerosis Unit, Neurology, Ramón y Cajal University Hospital, Madrid, Spain
| | - Manuel Comabella
- grid.411083.f0000 0001 0675 8654Neurology-Neuroimmunology Service, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Luciana Midaglia
- grid.411083.f0000 0001 0675 8654Neurology-Neuroimmunology Service, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - José Manuel García-Domínguez
- grid.410526.40000 0001 0277 7938Multiple Sclerosis Unit, Department of Neurology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Jennifer García-Arocha
- grid.414883.20000 0004 1767 1847Neuroimmuno-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - María Cristina Ortega
- grid.414883.20000 0004 1767 1847Neuroimmuno-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - Diego Clemente
- grid.414883.20000 0004 1767 1847Neuroimmuno-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45071 Toledo, Spain
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25
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Dagkonaki A, Papalambrou A, Avloniti M, Gkika A, Evangelidou M, Androutsou ME, Tselios T, Probert L. Maturation of circulating Ly6ChiCCR2+ monocytes by mannan-MOG induces antigen-specific tolerance and reverses autoimmune encephalomyelitis. Front Immunol 2022; 13:972003. [PMID: 36159850 PMCID: PMC9501702 DOI: 10.3389/fimmu.2022.972003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/03/2022] [Indexed: 11/30/2022] Open
Abstract
Autoimmune diseases affecting the CNS not only overcome immune privilege mechanisms that protect neural tissues but also peripheral immune tolerance mechanisms towards self. Together with antigen-specific T cells, myeloid cells are main effector cells in CNS autoimmune diseases such as multiple sclerosis, but the relative contributions of blood-derived monocytes and the tissue resident macrophages to pathology and repair is incompletely understood. Through the study of oxidized mannan-conjugated myelin oligodendrocyte glycoprotein 35-55 (OM-MOG), we show that peripheral maturation of Ly6ChiCCR2+ monocytes to Ly6ChiMHCII+PD-L1+ cells is sufficient to reverse spinal cord inflammation and demyelination in MOG-induced autoimmune encephalomyelitis. Soluble intradermal OM-MOG drains directly to the skin draining lymph node to be sequestered by subcapsular sinus macrophages, activates Ly6ChiCCR2+ monocytes to produce MHC class II and PD-L1, prevents immune cell trafficking to spinal cord, and reverses established lesions. We previously showed that protection by OM-peptides is antigen specific. Here, using a neutralizing anti-PD-L1 antibody in vivo and dendritic cell-specific Pdl1 knockout mice, we further demonstrate that PD-L1 in non-dendritic cells is essential for the therapeutic effects of OM-MOG. These results show that maturation of circulating Ly6ChiCCR2+ monocytes by OM-myelin peptides represents a novel mechanism of immune tolerance that reverses autoimmune encephalomyelitis.
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Affiliation(s)
- Anastasia Dagkonaki
- Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, Athens, Greece
| | - Athina Papalambrou
- Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, Athens, Greece
| | - Maria Avloniti
- Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, Athens, Greece
| | - Areti Gkika
- Department of Chemistry, University of Patras, Patras, Greece
| | - Maria Evangelidou
- Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, Athens, Greece
| | | | | | - Lesley Probert
- Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, Athens, Greece
- *Correspondence: Lesley Probert,
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Lv M, Zhuang X, Shao S, Li X, Cheng Y, Wu D, Wang X, Qiao T. Myeloid-Derived Suppressor Cells and CD68 +CD163 +M2-Like Macrophages as Therapeutic Response Biomarkers Are Associated with Plasma Inflammatory Cytokines: A Preliminary Study for Non-Small Cell Lung Cancer Patients in Radiotherapy. J Immunol Res 2022; 2022:3621496. [PMID: 35928634 PMCID: PMC9345704 DOI: 10.1155/2022/3621496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 05/27/2022] [Accepted: 06/16/2022] [Indexed: 12/24/2022] Open
Abstract
Background Recent studies show that myeloid-derived suppressor cells (MDSCs) and M2-like macrophages are involved in the treatment of tumors; however, their therapeutic response role is rarely known in non-small cell lung cancer (NSCLC) during radiotherapy. We aim to explore the dynamic alteration of the circulating MDSCs and M2-like macrophages, to examine their relationship, and to evaluate their therapeutic response value for NSCLC patients in radiotherapy. Methods Peripheral blood mononuclear cells from healthy controls and NSCLC patients with different radiotherapy phases were isolated to examine the circulating MDSCs and M2-like macrophages by flow cytometry. 40 plasma inflammatory cytokines were measured by multiplex ELISA. Results In comparison with healthy controls, the percentages of MDSCs and CD68+CD163+M2-like macrophages of NSCLC patients were significantly elevated and were distinctly higher in radiotherapy than in preradiotherapy. MDSCs were correlated positively with CD68+CD163+M2-like macrophages in NSCLC patients in radiotherapy and postradiotherapy. Especially, we found that in comparison with those in the poor group, the percentages of two cells in the good response group were markedly increased during radiotherapy and they had a significantly positive correlation. During radiotherapy, the proportions of MDSCs were clearly increased in adenocarcinoma patients and the percentages of CD68+CD163+M2-like macrophages were markedly elevated in squamous carcinoma patients. We found that after radiotherapy, the expressions of eotaxin, MIP-1β, MCP-1, and BLC were significantly increased in NSCLC patients. Further results showed that the low levels of eotaxin and TNF RII expression before radiotherapy could predict a good therapeutic response. IL-1ra and MIP-1β had a positive relation with MDSCs or CD68+CD163+M2-like macrophages in NSCLC patients during radiotherapy, and eotaxin was correlated with CD68+CD163+M2-like macrophages but not MDSCs in NSCLC patients after radiotherapy. Conclusions MDSCs and CD68+CD163+M2-like macrophages serve as therapeutic response biomarkers and are associated with the expressions of plasma inflammatory cytokines for NSCLC patients during radiotherapy.
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Affiliation(s)
- Minghe Lv
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Xibing Zhuang
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Shali Shao
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Xuan Li
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Yunfeng Cheng
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Duojiao Wu
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Xiangdong Wang
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Tiankui Qiao
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai 201508, China
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27
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Sakowska J, Arcimowicz Ł, Jankowiak M, Papak I, Markiewicz A, Dziubek K, Kurkowiak M, Kote S, Kaźmierczak-Siedlecka K, Połom K, Marek-Trzonkowska N, Trzonkowski P. Autoimmunity and Cancer-Two Sides of the Same Coin. Front Immunol 2022; 13:793234. [PMID: 35634292 PMCID: PMC9140757 DOI: 10.3389/fimmu.2022.793234] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 04/12/2022] [Indexed: 02/06/2023] Open
Abstract
Autoimmune disease results from the immune response against self-antigens, while cancer develops when the immune system does not respond to malignant cells. Thus, for years, autoimmunity and cancer have been considered as two separate fields of research that do not have a lot in common. However, the discovery of immune checkpoints and the development of anti-cancer drugs targeting PD-1 (programmed cell death receptor 1) and CTLA-4 (cytotoxic T lymphocyte antigen 4) pathways proved that studying autoimmune diseases can be extremely helpful in the development of novel anti-cancer drugs. Therefore, autoimmunity and cancer seem to be just two sides of the same coin. In the current review, we broadly discuss how various regulatory cell populations, effector molecules, genetic predisposition, and environmental factors contribute to the loss of self-tolerance in autoimmunity or tolerance induction to cancer. With the current paper, we also aim to convince the readers that the pathways involved in cancer and autoimmune disease development consist of similar molecular players working in opposite directions. Therefore, a deep understanding of the two sides of immune tolerance is crucial for the proper designing of novel and selective immunotherapies.
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Affiliation(s)
- Justyna Sakowska
- Department of Medical Immunology, Medical University of Gdańsk, Gdańsk, Poland
| | - Łukasz Arcimowicz
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | - Martyna Jankowiak
- Department of Medical Immunology, Medical University of Gdańsk, Gdańsk, Poland
| | - Ines Papak
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | - Aleksandra Markiewicz
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland
| | - Katarzyna Dziubek
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | - Małgorzata Kurkowiak
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | - Sachin Kote
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | | | - Karol Połom
- Department of Surgical Oncology, Medical University of Gdańsk, Gdańsk, Poland
| | - Natalia Marek-Trzonkowska
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
- Laboratory of Immunoregulation and Cellular Therapies, Department of Family Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Piotr Trzonkowski
- Department of Medical Immunology, Medical University of Gdańsk, Gdańsk, Poland
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28
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Calahorra L, Camacho-Toledano C, Serrano-Regal MP, Ortega MC, Clemente D. Regulatory Cells in Multiple Sclerosis: From Blood to Brain. Biomedicines 2022; 10:335. [PMID: 35203544 PMCID: PMC8961785 DOI: 10.3390/biomedicines10020335] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 01/26/2022] [Accepted: 01/27/2022] [Indexed: 02/01/2023] Open
Abstract
Multiple sclerosis (MS) is a chronic, autoimmune, and neurodegenerative disease of the central nervous system (CNS) that affects myelin. The etiology of MS is unclear, although a variety of environmental and genetic factors are thought to increase the risk of developing the disease. Historically, T cells were considered to be the orchestrators of MS pathogenesis, but evidence has since accumulated implicating B lymphocytes and innate immune cells in the inflammation, demyelination, and axonal damage associated with MS disease progression. However, more recently the importance of the protective role of immunoregulatory cells in MS has become increasingly evident, such as that of myeloid-derived suppressor cells (MDSCs), regulatory T (Treg) and B (Breg) cells, or CD56bright natural killer cells. In this review, we will focus on how peripheral regulatory cells implicated in innate and adaptive immune responses are involved in the physiopathology of MS. Moreover, we will discuss how these cells are thought to act and contribute to MS histopathology, also addressing their promising role as promoters of successful remyelination within the CNS. Finally, we will analyze how understanding these protective mechanisms may be crucial in the search for potential therapies for MS.
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Affiliation(s)
| | | | | | | | - Diego Clemente
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, 45071 Toledo, Spain; (L.C.); (C.C.-T.); (M.P.S.-R.); (M.C.O.)
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29
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Ganciclovir attenuates the onset and progression of experimental autoimmune uveitis by inhibiting infiltration of Th17 and inflammatory cells into the retina. Biochem Pharmacol 2022; 197:114917. [PMID: 35041813 DOI: 10.1016/j.bcp.2022.114917] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/07/2022] [Accepted: 01/10/2022] [Indexed: 11/22/2022]
Abstract
Noninfectious (autoimmune and immune-mediated) uveitis is one of the primary diseases leading to blindness in the world. Due to the limitation of current first-line drugs for clinical uveitis, novel drugs and targets against uveitis are urgently needed. Ganciclovir (GCV), an FDA-approved antiviral drug, is often used to treat cytomegalovirus-induced retinitis in clinical patients. Recently, GCV was found to suppress neuroinflammation via targeting STING signaling because the STING pathway plays a pivotal role in autoimmune diseases. However, until now, the effect of GCV on non-infectious uveitis has never been explored. In this work, using the rat experimental autoimmune uveitis (EAU) model, we first found STING to be highly expressed in infiltrating cells (CD68+, CD45+, and CD4+) and retinal glial cells (Iba1+ and GFAP+) of the immunized retina. More importantly, GCV treatment can significantly suppress the initiation and progression of EAU by inhibiting infiltration of Th17 and inflammatory cells into the retina. Mechanistically, we found that GCV could reverse the levels of pro-inflammatory factors (such as IL-1β) and chemokine-related factors (such as Cxcr3), possibly via targeting the STING pathway. The present results suggest that GCV may be considered as a novel therapeutic strategy against human uveitis.
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30
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Del Pilar C, Lebrón-Galán R, Pérez-Martín E, Pérez-Revuelta L, Ávila-Zarza CA, Alonso JR, Clemente D, Weruaga E, Díaz D. The Selective Loss of Purkinje Cells Induces Specific Peripheral Immune Alterations. Front Cell Neurosci 2021; 15:773696. [PMID: 34916910 PMCID: PMC8671039 DOI: 10.3389/fncel.2021.773696] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 10/27/2021] [Indexed: 11/13/2022] Open
Abstract
The progression of neurodegenerative diseases is reciprocally associated with impairments in peripheral immune responses. We investigated different contexts of selective neurodegeneration to identify specific alterations of peripheral immune cells and, at the same time, discover potential biomarkers associated to this pathological condition. Consequently, a model of human cerebellar degeneration and ataxia -the Purkinje Cell Degeneration (PCD) mouse- has been employed, as it allows the study of different processes of selective neuronal death in the same animal, i.e., Purkinje cells in the cerebellum and mitral cells in the olfactory bulb. Infiltrated leukocytes were studied in both brain areas and compared with those from other standardized neuroinflammatory models obtained by administering either gamma radiation or lipopolysaccharide. Moreover, both myeloid and lymphoid splenic populations were analyzed by flow cytometry, focusing on markers of functional maturity and antigen presentation. The severity and type of neural damage and inflammation affected immune cell infiltration. Leukocytes were more numerous in the cerebellum of PCD mice, being located predominantly within those cerebellar layers mostly affected by neurodegeneration, in a completely different manner than the typical models of induced neuroinflammation. Furthermore, the milder degeneration of the olfactory bulb did not foster leukocyte attraction. Concerning the splenic analysis, in PCD mice we found: (1) a decreased percentage of several myeloid cell subsets, and (2) a reduced mean fluorescence intensity in those myeloid markers related to both antigen presentation and functional maturity. In conclusion, the selective degeneration of Purkinje cells triggers a specific effect on peripheral immune cells, fostering both attraction and functional changes. This fact endorses the employment of peripheral immune cell populations as concrete biomarkers for monitoring different neuronal death processes.
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Affiliation(s)
- Carlos Del Pilar
- INCyL, Institute for Neuroscience of Castile and Leon, Universidad de Salamanca, Salamanca, Spain.,IBSAL, Institute of Biomedical Research of Salamanca, Salamanca, Spain
| | - Rafael Lebrón-Galán
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, Toledo, Spain.,SESCAM (Servicio de Salud de Castile-La-Mancha), Castilla-La Mancha, Spain
| | - Ester Pérez-Martín
- INCyL, Institute for Neuroscience of Castile and Leon, Universidad de Salamanca, Salamanca, Spain.,IBSAL, Institute of Biomedical Research of Salamanca, Salamanca, Spain
| | - Laura Pérez-Revuelta
- INCyL, Institute for Neuroscience of Castile and Leon, Universidad de Salamanca, Salamanca, Spain.,IBSAL, Institute of Biomedical Research of Salamanca, Salamanca, Spain
| | - Carmelo Antonio Ávila-Zarza
- IBSAL, Institute of Biomedical Research of Salamanca, Salamanca, Spain.,Applied Statistics Group, Department of Statistics, Universidad de Salamanca, Salamanca, Spain
| | - José Ramón Alonso
- INCyL, Institute for Neuroscience of Castile and Leon, Universidad de Salamanca, Salamanca, Spain.,IBSAL, Institute of Biomedical Research of Salamanca, Salamanca, Spain.,Instituto de Alta Investigación, Universidad de Tarapacá, Arica, Chile
| | - Diego Clemente
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, Toledo, Spain.,SESCAM (Servicio de Salud de Castile-La-Mancha), Castilla-La Mancha, Spain
| | - Eduardo Weruaga
- INCyL, Institute for Neuroscience of Castile and Leon, Universidad de Salamanca, Salamanca, Spain.,IBSAL, Institute of Biomedical Research of Salamanca, Salamanca, Spain
| | - David Díaz
- INCyL, Institute for Neuroscience of Castile and Leon, Universidad de Salamanca, Salamanca, Spain.,IBSAL, Institute of Biomedical Research of Salamanca, Salamanca, Spain
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31
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Targeting immunosuppressor cells with nanoparticles in autoimmunity: How far have we come to? Cell Immunol 2021; 368:104412. [PMID: 34340162 DOI: 10.1016/j.cellimm.2021.104412] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 12/24/2022]
Abstract
Autoimmunity is the assault of immune response towards self-antigens, resulting to inflammation and tissue injury. It is staged into three phases and caused by malfunction of immune tolerance. In our body, immune tolerance is synchronized by several immunosuppressor cells such as regulatory T cells and B cells as well as myeloid-derived suppressor cells, which are prominently dysregulated in autoimmunity. Hence, targeting these cell populations serve as a significant potential in the therapy of autoimmunity. Nanotechnology with its advantageous properties is shown to be a remarkable tool as drug delivery system in this field. This review focused on the development of therapeutics in autoimmune diseases utilizing various nanoparticles formulation based on two targeting approaches in autoimmunity, passive and active targeting. Lastly, this review outlined the approved present nanomedicines as well as in clinical evaluations and issues regarding the lack of translation of these nanomedicines into the market, despite the abundant of positive experimental observations.
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32
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Role of Myeloid-derived suppressor cell (MDSC) in autoimmunity and its potential as a therapeutic target. Inflammopharmacology 2021; 29:1307-1315. [PMID: 34283371 DOI: 10.1007/s10787-021-00846-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023]
Abstract
Myeloid suppressor cells (MDSCs) are an important class of immune-regulating cells that can suppress T cell function. Most of our knowledge about the function of MDSC comes from studies of cancer models. Recent studies, however, have greatly contributed to the description of MDSC involvement in autoimmune diseases. They are known as a cell population that may negatively affect immune responses by regulating the function of CD4+ and CD8+ cells, which makes them an attractive target for autoimmune diseases therapy. However, many questions about MDSC activation, differentiation, and inhibitory functions remain unanswered. In this study, we have summarized the role of MDSCs in various autoimmune diseases, and the potential of targeting them for therapeutic benefits has been discussed.
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33
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Davison LM, Alberto AA, Dand HA, Keller EJ, Patt M, Khan A, Dvorina N, White A, Sakurai N, Liegl LN, Vogl T, Jorgensen TN. S100a9 Protects Male Lupus-Prone NZBWF1 Mice From Disease Development. Front Immunol 2021; 12:681503. [PMID: 34220829 PMCID: PMC8248531 DOI: 10.3389/fimmu.2021.681503] [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: 03/16/2021] [Accepted: 06/01/2021] [Indexed: 11/13/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disorder disproportionally affecting women. A similar sex difference exists in the murine New Zealand Black/White hybrid model (NZBWF1) of SLE with all females, but only 30-40% of males, developing disease within the first year of life. Myeloid-derived suppressor cells (MDSCs) are prominent in NZBWF1 males and while depletion of these cells in males, but not females, promotes disease development, the mechanism of suppression remains unknown. S100a9, expressed by neutrophils and MDSCs, has previously been shown to exert immunosuppressive functions in cancer and inflammation. Here we investigated if S100a9 exerts immunosuppressive functions in NZBWF1 male and female mice. S100a9+/+, S100a9+/- and S100a9-/- NZBWF1 mice were followed for disease development for up to 8 months of age. Serum autoantibody levels, splenomegaly, lymphocyte activation, glomerulonephritis and proteinuria were measured longitudinally or at the time of harvest. In accordance with an immunosuppressive function of MDSCs in male mice, S100a9-deficient male NZBWF1 mice developed accelerated autoimmunity as indicated by increased numbers of differentiated effector B and T cells, elevated serum autoantibody levels, increased immune-complex deposition and renal inflammation, and accelerated development of proteinuria. In contrast, female mice showed either no response to S100a9-deficiency or even a slight reduction in disease symptoms. Furthermore, male, but not female, S100a9-/- NZBWF1 mice displayed an elevated type I interferon-induced gene signature, suggesting that S100a9 may dampen a pathogenic type I interferon signal in male mice. Taken together, S100a9 exerts an immunosuppressive function in male NZBWF1 mice effectively moderating lupus-like disease development via inhibition of type I interferon production, lymphocyte activation, autoantibody production and the development of renal disease.
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Affiliation(s)
- Laura M Davison
- Cleveland Clinic Lerner College of Medicine, Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Andres A Alberto
- Department of Inflammation and Immunity, Lerner Research Institute, NE40, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Hardik A Dand
- Department of Inflammation and Immunity, Lerner Research Institute, NE40, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Emma J Keller
- Cleveland Clinic Lerner College of Medicine, Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Madeline Patt
- Department of Inflammation and Immunity, Lerner Research Institute, NE40, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Ayesha Khan
- Department of Inflammation and Immunity, Lerner Research Institute, NE40, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Nina Dvorina
- Department of Inflammation and Immunity, Lerner Research Institute, NE40, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Alexandra White
- Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, United States
| | - Nodoka Sakurai
- Department of Inflammation and Immunity, Lerner Research Institute, NE40, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Lauren N Liegl
- Department of Inflammation and Immunity, Lerner Research Institute, NE40, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Thomas Vogl
- Institute of Immunology, University of Muenster, Muenster, Germany
| | - Trine N Jorgensen
- Department of Inflammation and Immunity, Lerner Research Institute, NE40, Cleveland Clinic Foundation, Cleveland, OH, United States
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34
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Ge Y, Cheng D, Jia Q, Xiong H, Zhang J. Mechanisms Underlying the Role of Myeloid-Derived Suppressor Cells in Clinical Diseases: Good or Bad. Immune Netw 2021; 21:e21. [PMID: 34277111 PMCID: PMC8263212 DOI: 10.4110/in.2021.21.e21] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 05/16/2021] [Accepted: 05/18/2021] [Indexed: 12/24/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) have strong immunosuppressive activity and are morphologically similar to conventional monocytes and granulocytes. The development and classification of these cells have, however, been controversial. The activation network of MDSCs is relatively complex, and their mechanism of action is poorly understood, creating an avenue for further research. In recent years, MDSCs have been found to play an important role in immune regulation and in effectively inhibiting the activity of effector lymphocytes. Under certain conditions, particularly in the case of tissue damage or inflammation, MDSCs play a leading role in the immune response of the central nervous system. In cancer, however, this can lead to tumor immune evasion and the development of related diseases. Under cancerous conditions, tumors often alter bone marrow formation, thus affecting progenitor cell differentiation, and ultimately, MDSC accumulation. MDSCs are important contributors to tumor progression and play a key role in promoting tumor growth and metastasis, and even reduce the efficacy of immunotherapy. Currently, a number of studies have demonstrated that MDSCs play a key regulatory role in many clinical diseases. In light of these studies, this review discusses the origin of MDSCs, the mechanisms underlying their activation, their role in a variety of clinical diseases, and their function in immune response regulation.
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Affiliation(s)
- Yongtong Ge
- Institute of Immunology and Molecular Medicine, Basic Medical School, Jining Medical University, Jining 272067, China
| | - Dalei Cheng
- Institute of Immunology and Molecular Medicine, Basic Medical School, Jining Medical University, Jining 272067, China
| | - Qingzhi Jia
- Affiliated Hospital of Jining Medical College, Jining Medical University, Jining 272067, China
| | - Huabao Xiong
- Institute of Immunology and Molecular Medicine, Basic Medical School, Jining Medical University, Jining 272067, China
| | - Junfeng Zhang
- Institute of Immunology and Molecular Medicine, Basic Medical School, Jining Medical University, Jining 272067, China
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35
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Fleck AK, Hucke S, Teipel F, Eschborn M, Janoschka C, Liebmann M, Wami H, Korn L, Pickert G, Hartwig M, Wirth T, Herold M, Koch K, Falk-Paulsen M, Dobrindt U, Kovac S, Gross CC, Rosenstiel P, Trautmann M, Wiendl H, Schuppan D, Kuhlmann T, Klotz L. Dietary conjugated linoleic acid links reduced intestinal inflammation to amelioration of CNS autoimmunity. Brain 2021; 144:1152-1166. [PMID: 33899089 PMCID: PMC8105041 DOI: 10.1093/brain/awab040] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 10/23/2020] [Accepted: 11/16/2020] [Indexed: 12/17/2022] Open
Abstract
A close interaction between gut immune responses and distant organ-specific autoimmunity including the CNS in multiple sclerosis has been established in recent years. This so-called gut–CNS axis can be shaped by dietary factors, either directly or via indirect modulation of the gut microbiome and its metabolites. Here, we report that dietary supplementation with conjugated linoleic acid, a mixture of linoleic acid isomers, ameliorates CNS autoimmunity in a spontaneous mouse model of multiple sclerosis, accompanied by an attenuation of intestinal barrier dysfunction and inflammation as well as an increase in intestinal myeloid-derived suppressor-like cells. Protective effects of dietary supplementation with conjugated linoleic acid were not abrogated upon microbiota eradication, indicating that the microbiome is dispensable for these conjugated linoleic acid-mediated effects. Instead, we observed a range of direct anti-inflammatory effects of conjugated linoleic acid on murine myeloid cells including an enhanced IL10 production and the capacity to suppress T-cell proliferation. Finally, in a human pilot study in patients with multiple sclerosis (n = 15, under first-line disease-modifying treatment), dietary conjugated linoleic acid-supplementation for 6 months significantly enhanced the anti-inflammatory profiles as well as functional signatures of circulating myeloid cells. Together, our results identify conjugated linoleic acid as a potent modulator of the gut–CNS axis by targeting myeloid cells in the intestine, which in turn control encephalitogenic T-cell responses.
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Affiliation(s)
- Ann-Katrin Fleck
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Stephanie Hucke
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Flavio Teipel
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Melanie Eschborn
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Claudia Janoschka
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Marie Liebmann
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Haleluya Wami
- Institute for Hygiene, University Hospital Münster, Münster, Germany
| | - Lisanne Korn
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Geethanjali Pickert
- Institute of Translational Immunology, University Medical Center Mainz, Mainz, Germany
| | - Marvin Hartwig
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Timo Wirth
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Martin Herold
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Kathrin Koch
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Maren Falk-Paulsen
- Institute of Clinical Molecular Biology, University of Kiel, Kiel, Germany
| | - Ulrich Dobrindt
- Institute for Hygiene, University Hospital Münster, Münster, Germany
| | - Stjepana Kovac
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Catharina C Gross
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, University of Kiel, Kiel, Germany
| | - Marcel Trautmann
- Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Heinz Wiendl
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology, University Medical Center Mainz, Mainz, Germany.,Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Tanja Kuhlmann
- Department of Neuropathology, University of Münster, Münster, Germany
| | - Luisa Klotz
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
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Reddy S, Tatiparti K, Sau S, Iyer AK. Recent advances in nano delivery systems for blood-brain barrier (BBB) penetration and targeting of brain tumors. Drug Discov Today 2021; 26:1944-1952. [PMID: 33865978 DOI: 10.1016/j.drudis.2021.04.008] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 01/24/2021] [Accepted: 04/08/2021] [Indexed: 02/09/2023]
Abstract
Gliomas constitute about 80% of brain tumors and have a meager two-year survival rate. The treatment options available are very few because of poor prognosis and a lack of targeted nanodelivery systems that can cross the blood-brain barrier (BBB) and the blood-tumor barrier. This short review attempts to clarify the challenges for delivery systems designed to cross the BBB, and provides a brief description of the different types of targeted nanodelivery system that have shown potential for success in delivering drugs to the brain. Further, this review describes the most recent studies that have developed nanoparticles for brain delivery in the past five years. We also provide an insight into the most recent clinical trials designed to assess the efficacy of these nanodelivery systems for glioma.
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Affiliation(s)
- Shriya Reddy
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; Northville High School, Northville, MI 48168, USA
| | - Katyayani Tatiparti
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Samaresh Sau
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; Molecular Imaging Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
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Candadai AA, Liu F, Fouda AY, Alfarhan M, Palani CD, Xu Z, Caldwell RB, Narayanan SP. Deletion of arginase 2 attenuates neuroinflammation in an experimental model of optic neuritis. PLoS One 2021; 16:e0247901. [PMID: 33735314 PMCID: PMC7971528 DOI: 10.1371/journal.pone.0247901] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 02/16/2021] [Indexed: 12/11/2022] Open
Abstract
Vision impairment due to optic neuritis (ON) is one of the major clinical presentations in Multiple Sclerosis (MS) and is characterized by inflammation and degeneration of the optic nerve and retina. Currently available treatments are only partially effective and have a limited impact on the neuroinflammatory pathology of the disease. A recent study from our laboratory highlighted the beneficial effect of arginase 2 (A2) deletion in suppressing retinal neurodegeneration and inflammation in an experimental model of MS. Utilizing the same model, the present study investigated the impact of A2 deficiency on MS-induced optic neuritis. Experimental autoimmune encephalomyelitis (EAE) was induced in wild-type (WT) and A2 knockout (A2-/-) mice. EAE-induced cellular infiltration, as well as activation of microglia and macrophages, were reduced in A2-/- optic nerves. Axonal degeneration and demyelination seen in EAE optic nerves were observed to be reduced with A2 deletion. Further, the lack of A2 significantly ameliorated astrogliosis induced by EAE. In conclusion, our findings demonstrate a critical involvement of arginase 2 in mediating neuroinflammation in optic neuritis and suggest the potential of A2 blockade as a targeted therapy for MS-induced optic neuritis.
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Affiliation(s)
- Amritha A. Candadai
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, United States of America
- Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States of America
- Charlie Norwood VA Medical Center, Augusta, GA, United States of America
| | - Fang Liu
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, United States of America
- Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States of America
- Charlie Norwood VA Medical Center, Augusta, GA, United States of America
- Vascular Biology Center, Augusta University, Augusta, GA, United States of America
| | - Abdelrahman Y. Fouda
- Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States of America
- Charlie Norwood VA Medical Center, Augusta, GA, United States of America
- Vascular Biology Center, Augusta University, Augusta, GA, United States of America
| | - Moaddey Alfarhan
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, United States of America
- Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States of America
- Charlie Norwood VA Medical Center, Augusta, GA, United States of America
| | - Chithra D. Palani
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, United States of America
- Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States of America
- Vascular Biology Center, Augusta University, Augusta, GA, United States of America
| | - Zhimin Xu
- Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States of America
- Vascular Biology Center, Augusta University, Augusta, GA, United States of America
| | - Ruth B. Caldwell
- Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States of America
- Vascular Biology Center, Augusta University, Augusta, GA, United States of America
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, United States of America
| | - S. Priya Narayanan
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, United States of America
- Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States of America
- Charlie Norwood VA Medical Center, Augusta, GA, United States of America
- Vascular Biology Center, Augusta University, Augusta, GA, United States of America
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, United States of America
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Dynamics of Central Remyelination and Treatment Evolution in a Model of Multiple Sclerosis with Optic Coherence Tomography. Int J Mol Sci 2021; 22:ijms22052440. [PMID: 33671012 PMCID: PMC7957639 DOI: 10.3390/ijms22052440] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/15/2021] [Accepted: 02/24/2021] [Indexed: 01/03/2023] Open
Abstract
The need for remyelinating drugs is essential for healing disabling diseases such as multiple sclerosis (MS). One of the reasons for the lack of this class of therapies is the impossibility to monitor remyelination in vivo, which is of utmost importance to perform effective clinical trials. Here, we show how optical coherence tomography (OCT), a cheap and non-invasive technique commonly used in ophthalmology, may be used to assess remyelination in vivo in MS patients. Our pioneer approach validates OCT as a technique to study remyelination of the optic nerve and reflects what is occurring in non-accessible central nervous system (CNS) structures, like the spinal cord. In this study we used the orally bioavailable small molecule VP3.15, confirming its therapeutical potential as a neuroprotective, anti-inflammatory, and probably remyelinating drug for MS. Altogether, our results confirm the usefulness of OCT to monitor the efficacy of remyelinating therapies in vivo and underscore the relevance of VP3.15 as a potential disease modifying drug for MS therapy.
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39
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The role of myeloid-derived suppressor cells in rheumatoid arthritis: An update. Life Sci 2021; 269:119083. [PMID: 33482191 DOI: 10.1016/j.lfs.2021.119083] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 12/27/2020] [Accepted: 01/14/2021] [Indexed: 12/12/2022]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease that generally affects the joints. In the late stages of the disease, it can be associated with several complications. Although the exact etiology of RA is unknown, various studies have been performed to understand better the immunological mechanisms involved in the pathogenesis of RA. At the onset of the disease, various immune cells migrate to the joints and increase the recruitment of immune cells to the joints by several immunological mediators such as cytokines and chemokines. The function of specific immune cells in RA is well-established. The shift of immune responses to Th1 or Th17 is one of the most essential factors in the development of RA. Myeloid-derived suppressor cells (MDSCs), as a heterogeneous population of myeloid cells, play a regulatory role in the immune system that inhibits T cell activity through several mechanisms. Various studies have been performed on the function of these cells in RA, which in some cases have yielded conflicting results. Therefore, the purpose of this review article is to comprehensively understand the pro-inflammatory and anti-inflammatory functions of MDSCs in the pathogenesis of RA.
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Melero-Jerez C, Fernández-Gómez B, Lebrón-Galán R, Ortega MC, Sánchez-de Lara I, Ojalvo AC, Clemente D, de Castro F. Myeloid-derived suppressor cells support remyelination in a murine model of multiple sclerosis by promoting oligodendrocyte precursor cell survival, proliferation, and differentiation. Glia 2020; 69:905-924. [PMID: 33217041 PMCID: PMC7894183 DOI: 10.1002/glia.23936] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 11/05/2020] [Accepted: 11/06/2020] [Indexed: 02/06/2023]
Abstract
The most frequent variant of multiple sclerosis (MS) is the relapsing–remitting form, characterized by symptomatic phases followed by periods of total/partial recovery. Hence, it is possible that these patients can benefit from endogenous agents that control the inflammatory process and favor spontaneous remyelination. In this context, there is increasing interest in the role of myeloid‐derived suppressor cells (MDSCs) during the clinical course of experimental autoimmune encephalomyelitis (EAE). MDSCs speed up infiltrated T‐cell anergy and apoptosis. In different animal models of MS, a milder disease course is related to higher presence/density of MDSCs in the periphery, and smaller demyelinated lesions in the central nervous system (CNS). These observations lead us to wonder whether MDSCs might not only exert an anti‐inflammatory effect but might also have direct influence on oligodendrocyte precursor cells (OPCs) and remyelination. In the present work, we reveal for the first time the relationship between OPCs and MDSCs in EAE, relationship that is guided by the distance from the inflammatory core. We describe the effects of MDSCs on survival, proliferation, as well as potent promoters of OPC differentiation toward mature phenotypes. We show for the first time that osteopontin is remarkably present in the analyzed secretome of MDSCs. The ablation of this cue from MDSCs‐secretome demonstrates that osteopontin is the main MDSC effector on these oligodendroglial cells. These data highlight a crucial pathogenic interaction between innate immunity and the CNS, opening ways to develop MDSC‐ and/or osteopontin‐based therapies to promote effective myelin preservation and repair in MS patients.
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Affiliation(s)
- Carolina Melero-Jerez
- Instituto Cajal-CSIC, Madrid, Spain.,Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos-SESCAM, Toledo, Spain
| | | | - Rafael Lebrón-Galán
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos-SESCAM, Toledo, Spain
| | - Maria Cristina Ortega
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos-SESCAM, Toledo, Spain
| | - Irene Sánchez-de Lara
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos-SESCAM, Toledo, Spain
| | - Ana Cristina Ojalvo
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos-SESCAM, Toledo, Spain
| | - Diego Clemente
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos-SESCAM, Toledo, Spain
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41
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Wang Z, Zheng G, Li G, Wang M, Ma Z, Li H, Wang XY, Yi H. Methylprednisolone alleviates multiple sclerosis by expanding myeloid-derived suppressor cells via glucocorticoid receptor β and S100A8/9 up-regulation. J Cell Mol Med 2020; 24:13703-13714. [PMID: 33094923 PMCID: PMC7753844 DOI: 10.1111/jcmm.15928] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 08/17/2020] [Accepted: 09/05/2020] [Indexed: 02/06/2023] Open
Abstract
Methylprednisolone is an effective drug in the treatment of autoimmune disease, such as multiple sclerosis (MS), due to long‐acting anti‐inflammatory, antiallergic and immunosuppressant. Previous studies have noted the importance of myeloid‐derived suppressor cells (MDSC) in MS progression. However, it is still not known whether methylprednisolone could influence the ratio and function of MDSC during MS treatment. In the current study, we found an increased ratio of MDSC at the onset of EAE in mice model; but methylprednisolone pulse therapy (MPPT) did not alter the percentage and suppressive function of MDSC during disease attenuation. However, the percentage of G‐MDSC in PBMC significantly increased in patients with MS. Surprisingly, relapsing MS patients showed a significant increase in both M‐MDSC and G‐MDSC after MPPT. The disease remission positively correlated expansion of MDSC and expression of arginase‐1. Additionally, MPPT reduced the expression of inhibitory glucocorticoid (GCs) receptor β subunit on MDSC while elevating serum levels of immune regulatory S100A8/A9 heterodimer. Thus, MDSC dynamics and function in mouse EAE differ from those in human MS during MPPT. Our study suggested that GCs treatment may help relieve the acute phase of MS by expanding MDSC through up‐regulating of GR signalling and S100A8/A9 heterodimers.
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Affiliation(s)
- Zhongkun Wang
- Central Laboratory, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Organ Regeneration and Transplantation, Ministry of Education, Changchun, China.,Vasculocardiology Department, The Second Hospital of Jilin University, Changchun, China
| | - Ge Zheng
- Hepatopancreatobiliary Surgery Department, The Second Hospital of Jilin University, Changchun, China
| | - Guangjian Li
- Neurology Department, The First Hospital of Jilin University, Changchun, China
| | - Mengkun Wang
- Pediatric Department, The First Hospital of Jilin University, Changchun, China
| | - Zhanchuan Ma
- Central Laboratory, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Organ Regeneration and Transplantation, Ministry of Education, Changchun, China
| | - Huimin Li
- Central Laboratory, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Organ Regeneration and Transplantation, Ministry of Education, Changchun, China.,Clinical Laboratory, The Second Hospital of Jilin University, Changchun, China
| | - Xiang-Yang Wang
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.,Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Huanfa Yi
- Central Laboratory, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Organ Regeneration and Transplantation, Ministry of Education, Changchun, China
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42
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Activated neutrophils exert myeloid-derived suppressor cell activity damaging T cells beyond repair. Blood Adv 2020; 3:3562-3574. [PMID: 31738831 DOI: 10.1182/bloodadvances.2019031609] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 09/02/2019] [Indexed: 12/20/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) have the capacity to suppress T-cell-mediated immune responses and impact the clinical outcome of cancer, infections, and transplantation settings. Although MDSCs were initially described as bone marrow-derived immature myeloid cells (either monocytic or granulocytic MDSCs), mature neutrophils have been shown to exert MDSC activity toward T cells in ways that remain unclear. In this study, we demonstrated that human neutrophils from both healthy donors and cancer patients do not exert MDSC activity unless they are activated. By using neutrophils with genetically well-defined defects, we found that reactive oxygen species (ROS) and granule-derived constituents are required for MDSC activity after direct CD11b-dependent interactions between neutrophils and T cells. In addition to these cellular interactions, neutrophils are engaged in the uptake of pieces of T-cell membrane, a process called trogocytosis. Together, these interactions led to changes in T-cell morphology, mitochondrial dysfunction, and adenosine triphosphate depletion, as indicated by electron microscopy, mass spectrometry, and metabolic parameters. Our studies characterize the different steps by which activated mature neutrophils induce functional T-cell nonresponsiveness and irreparable cell damage.
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Nichols JM, Kummari E, Sherman J, Yang EJ, Dhital S, Gilfeather C, Yray G, Morgan T, Kaplan BLF. CBD Suppression of EAE Is Correlated with Early Inhibition of Splenic IFN-γ + CD8+ T Cells and Modest Inhibition of Neuroinflammation. J Neuroimmune Pharmacol 2020; 16:346-362. [PMID: 32440886 DOI: 10.1007/s11481-020-09917-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 04/03/2020] [Indexed: 01/08/2023]
Abstract
In this study cannabidiol (CBD) was administered orally to determine its effects and mechanisms in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). We hypothesized that 75 mg/kg of oral CBD given for 5 days after initiation of disease would reduce EAE severity through suppression of either the early peripheral immune or late neuroimmune response. EAE was induced in C57BL/6 mice at two different magnitudes, and peripheral inflammatory and neuroinflammatory responses were measured at days 3, 10, and 18. Th1, Th17, Tc1, Tc17, Tregs, and myeloid derived suppressor cells (MDSC) were identified from the lymph nodes and spleens of each mouse to determine if CBD altered the suppressor cell or inflammatory cell populations in secondary lymphoid tissues. Additionally, neuroinflammation was identified in brain and spinal cord tissues using various immunohistochemical techniques and flow cytometry. Early treatment of EAE with oral CBD reduced clinical disease at the day 18 timepoint which correlated with a significant decrease in the percentage of MOG35-55 specific IFN-γ producing CD8+ T cells in the spleen at day 10. Analysis of both T cell infiltration and lesion size within the spinal cord also showed a moderate reduction in neuroinflammation within the central nervous system (CNS). These results provide evidence that oral CBD suppressed the peripheral immune response that precedes neuroinflammation; however, analysis of the neuroinflammatory endpoints also suggest that the modest reduction in neuroinflammation was only partially responsible for CBD's neuroprotective capability. Graphical Abstract CBD was administered orally for the first 5 days following initiation of EAE. CBD attenuated clinical disease, and we found that CBD suppressed IFN-γ producing CD8+ T cells in the spleen at day 10. There was also modest suppression of neuroinflammation. Together these data demonstrate that early, oral administration of CBD protected mice from disease, but the modest effects on neuroinflammation suggest other mechanisms participate in CBD's neuroprotective effect in EAE.
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Affiliation(s)
- James M Nichols
- Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA
| | - Evangel Kummari
- Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA
| | - Jessica Sherman
- Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA
| | - Eun-Ju Yang
- Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA
| | - Saphala Dhital
- Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA
| | - Christa Gilfeather
- Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA
| | - Gabriella Yray
- Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA
| | - Timothy Morgan
- Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA
| | - Barbara L F Kaplan
- Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA.
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44
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Melero-Jerez C, Alonso-Gómez A, Moñivas E, Lebrón-Galán R, Machín-Díaz I, de Castro F, Clemente D. The proportion of myeloid-derived suppressor cells in the spleen is related to the severity of the clinical course and tissue damage extent in a murine model of multiple sclerosis. Neurobiol Dis 2020; 140:104869. [PMID: 32278882 DOI: 10.1016/j.nbd.2020.104869] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 01/28/2020] [Accepted: 04/07/2020] [Indexed: 02/07/2023] Open
Abstract
Multiple Sclerosis (MS) is the second cause of paraplegia among young adults, after all types of CNS traumatic lesions. In its most frequent relapsing-remitting form, the severity of the disease course is very heterogeneous, and its reliable evaluation remains a key issue for clinicians. Myeloid-Derived sSuppressor Cells (MDSCs) are immature myeloid cells that suppress the inflammatory response, a phenomenon related to the resolution or recovery of the clinical symptoms associated with experimental autoimmune encephalomyelitis (EAE), the most common model for MS. Here, we establish the severity index as a new parameter for the clinical assessment in EAE. It is derived from the relationship between the maximal clinical score and the time elapsed since disease onset. Moreover, we relate this new index with several histopathological hallmarks in EAE and with the peripheral content of MDSCs. Based on this new parameter, we show that the splenic MDSC content is related to the evolution of the clinical course of EAE, ranging from mild to severe. Indeed, when the severity index indicates a severe disease course, EAE mice display more intense lymphocyte infiltration, demyelination and axonal damage. A direct correlation was drawn between the MDSC population in the peripheral immune system, and the preservation of myelin and axons, which was also correlated with T cell apoptosis within the CNS (being these cells the main target for MDSC suppression). The data presented clearly indicated that the severity index is a suitable tool to analyze disease severity in EAE. Moreover, our data suggest a clear relationship between circulating MDSC enrichment and disease outcome, opening new perspectives for the future targeting of this population as an indicator of MS severity.
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Affiliation(s)
- Carolina Melero-Jerez
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, 45071 Toledo, Spain; Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, Avenida Doctor Arce 37, 28002 Madrid, Spain
| | - Aitana Alonso-Gómez
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - Esther Moñivas
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - Rafael Lebrón-Galán
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - Isabel Machín-Díaz
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - Fernando de Castro
- Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, Avenida Doctor Arce 37, 28002 Madrid, Spain.
| | - Diego Clemente
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, 45071 Toledo, Spain.
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45
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Ruiz F, Vigne S, Pot C. Resolution of inflammation during multiple sclerosis. Semin Immunopathol 2019; 41:711-726. [PMID: 31732775 PMCID: PMC6881249 DOI: 10.1007/s00281-019-00765-0] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 09/27/2019] [Indexed: 12/14/2022]
Abstract
Multiple sclerosis (MS) is a frequent autoimmune demyelinating disease of the central nervous system (CNS). There are three clinical forms described: relapsing-remitting multiple sclerosis (RRMS), the most common initial presentation (85%) among which, if not treated, about half will transform, into the secondary progressive multiple sclerosis (SPMS) and the primary progressive MS (PPMS) (15%) that is directly progressive without superimposed clinical relapses. Inflammation is present in all subsets of MS. The relapsing/remitting form could represent itself a particular interest for the study of inflammation resolution even though it remains incomplete in MS. Successful resolution of acute inflammation is a highly regulated process and dependent on mechanisms engaged early in the inflammatory response that are scarcely studied in MS. Moreover, recent classes of disease-modifying treatment (DMTs) that are effective against RRMS act by re-establishing the inflammatory imbalance, taking advantage of the pre-existing endogenous suppressor. In this review, we will discuss the active role of regulatory immune cells in inflammation resolution as well as the role of tissue and non-hematopoietic cells as contributors to inflammation resolution. Finally, we will explore how DMTs, more specifically induction therapies, impact the resolution of inflammation during MS.
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Affiliation(s)
- F Ruiz
- Laboratories of Neuroimmunology, Neuroscience Research Center and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Chemin des Boveresses 155, 1066, Epalinges, Switzerland
| | - S Vigne
- Laboratories of Neuroimmunology, Neuroscience Research Center and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Chemin des Boveresses 155, 1066, Epalinges, Switzerland
| | - C Pot
- Laboratories of Neuroimmunology, Neuroscience Research Center and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Chemin des Boveresses 155, 1066, Epalinges, Switzerland.
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46
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Consonni FM, Porta C, Marino A, Pandolfo C, Mola S, Bleve A, Sica A. Myeloid-Derived Suppressor Cells: Ductile Targets in Disease. Front Immunol 2019; 10:949. [PMID: 31130949 PMCID: PMC6509569 DOI: 10.3389/fimmu.2019.00949] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 04/12/2019] [Indexed: 12/15/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells with major regulatory functions and rise during pathological conditions, including cancer, infections and autoimmune conditions. MDSC expansion is generally linked to inflammatory processes that emerge in response to stable immunological stress, which alter both magnitude and quality of the myelopoietic output. Inability to reinstate physiological myelopoiesis would fall in an “emergency state” that perpetually reprograms myeloid cells toward suppressive functions. While differentiation and reprogramming of myeloid cells toward an immunosuppressive phenotype can be considered the result of a multistep process that originates in the bone marrow and culminates in the tumor microenvironment, the identification of its driving events may offer potential therapeutic approaches in different pathologies. Indeed, whereas expansion of MDSCs, in both murine and human tumor bearers, results in reduced immune surveillance and antitumor cytotoxicity, placing an obstacle to the effectiveness of anticancer therapies, adoptive transfer of MDSCs has shown therapeutic benefits in autoimmune disorders. Here, we describe relevant mechanisms of myeloid cell reprogramming leading to generation of suppressive MDSCs and discuss their therapeutic ductility in disease.
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Affiliation(s)
| | - Chiara Porta
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Novara, Italy.,Center for Translational Research on Autoimmune and Allergic Diseases (CAAD), University of Piemonte Orientale, Novara, Italy
| | - Arianna Marino
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Novara, Italy
| | - Chiara Pandolfo
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Novara, Italy
| | - Silvia Mola
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Novara, Italy.,Center for Translational Research on Autoimmune and Allergic Diseases (CAAD), University of Piemonte Orientale, Novara, Italy
| | - Augusto Bleve
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Novara, Italy
| | - Antonio Sica
- Humanitas Clinical and Research Center, Rozzano, Italy.,Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Novara, Italy
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Salminen A, Kaarniranta K, Kauppinen A. Immunosenescence: the potential role of myeloid-derived suppressor cells (MDSC) in age-related immune deficiency. Cell Mol Life Sci 2019; 76:1901-1918. [PMID: 30788516 PMCID: PMC6478639 DOI: 10.1007/s00018-019-03048-x] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 01/25/2019] [Accepted: 02/14/2019] [Indexed: 12/17/2022]
Abstract
The aging process is associated with chronic low-grade inflammation in both humans and rodents, commonly called inflammaging. At the same time, there is a gradual decline in the functional capacity of adaptive and innate immune systems, i.e., immunosenescence, a process not only linked to the aging process, but also encountered in several pathological conditions involving chronic inflammation. The hallmarks of immunosenescence include a decline in the numbers of naïve CD4+ and CD8+ T cells, an imbalance in the T cell subsets, and a decrease in T cell receptor (TCR) repertoire and signaling. Correspondingly, there is a decline in B cell lymphopoiesis and a reduction in antibody production. The age-related changes are not as profound in innate immunity as they are in adaptive immunity. However, there are distinct functional deficiencies in dendritic cells, natural killer cells, and monocytes/macrophages with aging. Interestingly, the immunosuppression induced by myeloid-derived suppressor cells (MDSC) in diverse inflammatory conditions also targets mainly the T and B cell compartments, i.e., inducing very similar alterations to those present in immunosenescence. Here, we will compare the immune profiles induced by immunosenescence and the MDSC-driven immunosuppression. Given that the appearance of MDSCs significantly increases with aging and MDSCs are the enhancers of other immunosuppressive cells, e.g., regulatory T cells (Tregs) and B cells (Bregs), it seems likely that MDSCs might remodel the immune system, thus preventing excessive inflammation with aging. We propose that MDSCs are potent inducers of immunosenescence.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
| | - Kai Kaarniranta
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
- Department of Ophthalmology, Kuopio University Hospital, KYS, P.O. Box 100, 70029, Kuopio, Finland
| | - Anu Kauppinen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
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Melero-Jerez C, Suardíaz M, Lebrón-Galán R, Marín-Bañasco C, Oliver-Martos B, Machín-Díaz I, Fernández Ó, de Castro F, Clemente D. The presence and suppressive activity of myeloid-derived suppressor cells are potentiated after interferon-β treatment in a murine model of multiple sclerosis. Neurobiol Dis 2019; 127:13-31. [PMID: 30798007 DOI: 10.1016/j.nbd.2019.02.014] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 12/13/2018] [Accepted: 02/20/2019] [Indexed: 02/06/2023] Open
Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the human central nervous system (CNS), mainly affecting young adults. Among the immunomodulatory disease modifying treatments approved up to date to treat MS, IFN-β remains to be one of the most widely prescribed for the Relapsing-Remitting (RR) variant of the disease, although its mechanism of action is still partially understood. RR-MS variant is characterized by phases with increasing neurological symptoms (relapses) followed by periods of total or partial recovery (remissions), which implies the existence of immunomodulatory agents to promote the relapsing-to-remitting transition. Among these agents, it has been described the immunosuppressive role of a heterogeneous population of immature myeloid cells, namely the myeloid-derived suppressor cells (MDSCs) during the clinical course of the experimental autoimmune encephalomyelitis (EAE), the most used MS model to study RRMS. However, it is still unknown how the current MS disease modifying treatments, e.g. IFN- β, affects to MDSCs number or activity. Our present results show that a single injection of IFN-β at the onset of the clinical course reduces the severity of the EAE, enhancing the presence of MDSCs within the smaller demyelinated areas. Moreover, the single dose of IFN-β promotes MDSC immunosuppressive activity both in vivo and in vitro, augmenting T cell apoptosis. Finally, we show that IFN-ß preserves MDSC immaturity, preventing their differentiation to mature and less suppressive myeloid cell subsets. Taking together, all these data add new insights into the mechanism of IFN-β treatment in EAE and point to MDSCs as a putative endogenous mediator of its beneficial role in this animal model of MS.
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Affiliation(s)
- Carolina Melero-Jerez
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, 45071 Toledo, Spain; Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, Avenida Doctor Arce 37, 28002 Madrid, Spain
| | - Margarita Suardíaz
- Unidad de Gestión Clínica Inter-centros de Neurociencias, Laboratorio de Investigación y Servicio de Neurología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Madrid, Spain
| | - Rafael Lebrón-Galán
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - Carmen Marín-Bañasco
- Unidad de Gestión Clínica Inter-centros de Neurociencias, Laboratorio de Investigación y Servicio de Neurología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Madrid, Spain
| | - Begoña Oliver-Martos
- Unidad de Gestión Clínica Inter-centros de Neurociencias, Laboratorio de Investigación y Servicio de Neurología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Madrid, Spain
| | - Isabel Machín-Díaz
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, 45071 Toledo, Spain
| | - Óscar Fernández
- Unidad de Gestión Clínica Inter-centros de Neurociencias, Laboratorio de Investigación y Servicio de Neurología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Madrid, Spain
| | - Fernando de Castro
- Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, Avenida Doctor Arce 37, 28002 Madrid, Spain.
| | - Diego Clemente
- Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, 45071 Toledo, Spain.
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Li M, Zhu D, Wang T, Xia X, Tian J, Wang S. Roles of Myeloid-Derived Suppressor Cell Subpopulations in Autoimmune Arthritis. Front Immunol 2018; 9:2849. [PMID: 30564242 PMCID: PMC6288996 DOI: 10.3389/fimmu.2018.02849] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 11/19/2018] [Indexed: 12/29/2022] Open
Abstract
Emerging evidence suggests the promise of the use of myeloid-derived suppressor cells (MDSCs) in inflammatory disorders based on their unique immune-intervention properties. However, the roles of MDSCs in autoimmune arthritis are not completely understood. Indeed, their immunosuppressive functions in arthritic conditions remain controversial, with heterogeneity among MDSCs and differential effects among subpopulations receiving much attention. As a result, it is necessary to determine the roles of MDSC subpopulations in autoimmune arthritis to clarify their diagnostic and therapeutic potential. Interestingly, in the inflammation niche of autoimmune arthritis, each MDSC subpopulation can exhibit both alternatives of a given characteristic. Moreover, polymorphonuclear MDSCs (PMN-MDSCs) are likely to be more suppressive and stable compared with monocytic MDSCs (MO-MDSCs). Although various important cytokines associated with the differentiation of MDSCs or MDSC subpopulations from immature myeloid precursors, such as granulocyte colony-stimulating factor (G-CSF), have been largely applied in external inductive systems, their roles are not entirely clear. Moreover, MDSC-based clinical treatments in rheumatoid arthritis (RA) continue to represent a significant challenge, as also reported for other autoimmune diseases. In this review, we describe the effects and actions of MDSC subpopulations on the development of autoimmune arthritis and analyze several types of MDSC-based therapeutic strategies to provide comprehensive information regarding immune networks and a foundation for more effective protocols for autoimmune arthritis.
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Affiliation(s)
- Min Li
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Dongwei Zhu
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Tingting Wang
- Department of Laboratory Medicine, Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Children's Hospital, Wuxi, China
| | - Xueli Xia
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Jie Tian
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Shengjun Wang
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
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Jiao Y, Li XY, Liu J. A New Approach to Cerebral Palsy Treatment: Discussion of the Effective Components of Umbilical Cord Blood and its Mechanisms of Action. Cell Transplant 2018; 28:497-509. [PMID: 30384766 PMCID: PMC7103597 DOI: 10.1177/0963689718809658] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cerebral palsy (CP) includes a group of persistent non-progressive disorders
affecting movement, muscle tone, and/or posture. The total economic loss during
the life-span of an individual with CP places a heavy financial burden on such
patients and their families worldwide; however, a complete cure is still
lacking. Umbilical cord blood (UCB)-based interventions are emerging as a
scientifically plausible treatment and possible cure for CP. Stem cells have
been used in many experimental CP animal models and achieved good results.
Compared with other types of stem cells, those from UCB have advantages in terms
of treatment safety and efficacy, ethics, non-neoplastic proliferation,
accessibility, ease of preservation, and regulation of immune responses, based
on findings in animal models and clinical trials. Currently, the use of
UCB-based interventions for CP is limited as the components of UCB are complex
and possess different therapeutic mechanisms. These can be categorized by three
aspects: homing and neuroregeneration, trophic factor secretion, and
neuroprotective effects. Our review summarizes the features of active components
of UCB and their therapeutic mechanism of action. This review highlights current
research findings and clinical evidence regarding UCB that contribute to
treatment suggestions, inform decision-making for therapeutic interventions, and
help to direct future research.
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Affiliation(s)
- Yang Jiao
- 1 Stem Cell Clinical Research Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Xiao-Yan Li
- 1 Stem Cell Clinical Research Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Jing Liu
- 1 Stem Cell Clinical Research Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China
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