scholarly journals Interleukin-26, preferentially produced by TH17 lymphocytes, regulates CNS barrier function

2020 ◽  
Vol 7 (6) ◽  
pp. e870 ◽  
Author(s):  
Bieke Broux ◽  
Stephanie Zandee ◽  
Elizabeth Gowing ◽  
Marc Charabati ◽  
Marc-André Lécuyer ◽  
...  
Keyword(s):  
Immune Cell ◽  
Postmortem Brain ◽  
Autoimmune Encephalomyelitis ◽  
Th17 Lymphocytes ◽  
Postmortem Brain Tissue ◽  
Human And Mouse ◽  
Experimental Autoimmune

ObjectiveTo investigate the involvement of interleukin (IL)-26 in neuroinflammatory processes in multiple sclerosis (MS), in particular in blood-brain barrier (BBB) integrity.MethodsExpression of IL-26 was measured in serum, CSF, in vitro differentiated T helper (TH) cell subsets, and postmortem brain tissue of patients with MS and controls by ELISA, quantitative PCR, and immunohistochemistry. Primary human and mouse BBB endothelial cells (ECs) were treated with IL-26 in vitro and assessed for BBB integrity. RNA sequencing was performed on IL-26–treated human BBB ECs. Myelin oligodendrocyte glycoprotein35–55 experimental autoimmune encephalomyelitis (EAE) mice were injected IP with IL-26. BBB leakage and immune cell infiltration were assessed in the CNS of these mice using immunohistochemistry and flow cytometry.ResultsIL-26 expression was induced in TH lymphocytes by TH17-inducing cytokines and was upregulated in the blood and CSF of patients with MS. CD4+IL-26+ T lymphocytes were found in perivascular infiltrates in MS brain lesions, and both receptor chains for IL-26 (IL-10R2 and IL-20R1) were detected on BBB ECs in vitro and in situ. In contrast to IL-17 and IL-22, IL-26 promoted integrity and reduced permeability of BBB ECs in vitro and in vivo. In EAE, IL-26 reduced disease severity and proinflammatory lymphocyte infiltration into the CNS, while increasing infiltration of Tregs.ConclusionsOur study demonstrates that although IL-26 is preferentially expressed by TH17 lymphocytes, it promotes BBB integrity in vitro and in vivo and is protective in chronic EAE, highlighting the functional diversity of cytokines produced by TH17 lymphocytes.

scholarly journals Induction of Golli-MBP Expression in CNS Macrophages During Acute LPS-Induced CNS Inflammation and Experimental Autoimmune Encephalomyelitis (EAE)

2007 ◽  
Vol 7 ◽  
pp. 112-120 ◽  
Author(s):  
Tracey L. Papenfuss ◽  
J. Cameron Thrash ◽  
Patricia E. Danielson ◽  
Pamela E. Foye ◽  
Brian S. Hllbrush ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Cell Type ◽  
Autoimmune Encephalomyelitis ◽  
Cns Inflammation ◽  
Cell Type Specific ◽  
Candidate Molecule ◽  
Experimental Autoimmune

Microglia are the tissue macrophages of the CNS. Microglial activation coupled with macrophage infiltration is a common feature of many classic neurodegenerative disorders. The absence of cell-type specific markers has confounded and complicated the analysis of cell-type specific contributions toward the onset, progression, and remission of neurodegeneration. Molecular screens comparing gene expression in cultured microglia and macrophages identified Golli-myelin basic protein (MBP) as a candidate molecule enriched in peripheral macrophages.In situhybridization analysis of LPS/IFNg and experimental autoimmune encephalomyelitis (EAE)–induced CNS inflammation revealed that only a subset of CNS macrophages express Golli-MBP. Interestingly, the location and morphology of Golli-MBP+ CNS macrophages differs between these two models of CNS inflammation. These data demonstrate the difficulties of extendingin vitroobservations toin vivobiology and concretely illustrate the complex heterogeneity of macrophage activation states present in region- and stage-specific phases of CNS inflammation. Taken altogether, these are consistent with the emerging picture that the phenotype of CNS macrophages is actively defined by their molecular interactions with the CNS microenvironment.

scholarly journals c-Jun N-Terminal Kinase as a Therapeutic Target in Experimental Autoimmune Encephalomyelitis

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2154
Author(s):  
Maud Bagnoud ◽  
Myriam Briner ◽  
Jana Remlinger ◽  
Ivo Meli ◽  
Sara Schuetz ◽  
...  
Keyword(s):  
Spinal Cord ◽  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cell ◽  
Disease Onset ◽  
Autoimmune Encephalomyelitis ◽  
Necrosis Factor Alpha ◽  
Experimental Autoimmune

c-Jun N-terminal kinase (JNK) is upregulated during multiple sclerosis relapses and at the peak of experimental autoimmune encephalomyelitis (EAE). We aim to investigate the effects of pharmacological pan-JNK inhibition on the course of myelin oligodendrocyte glycoprotein (MOG35-55) EAE disease using in vivo and in vitro experimental models. EAE was induced in female C57BL/6JRj wild type mice using MOG35-55. SP600125 (SP), a reversible adenosine triphosphate competitive pan-JNK inhibitor, was then given orally after disease onset. Positive correlation between SP plasma and brain concentration was observed. Nine, but not three, consecutive days of SP treatment led to a significant dose-dependent decrease of mean cumulative MOG35-55 EAE severity that was associated with increased mRNA expression of interferon gamma (INF-γ) and tumor necrosis factor alpha (TNF-α) in the spinal cord. On a histological level, reduced spinal cord immune cell-infiltration predominantly of CD3+ T cells as well as increased activity of Iba1+ cells were observed in treated animals. In addition, in vitro incubation of murine and human CD3+ T cells with SP resulted in reduced T cell apoptosis and proliferation. In conclusion, our study demonstrates that pharmacological pan-JNK inhibition might be a treatment strategy for autoimmune central nervous system demyelination.

scholarly journals The survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lihi Radomir ◽  
Matthias P. Kramer ◽  
Michal Perpinial ◽  
Nofar Schottlender ◽  
Stav Rabani ◽  
...  
Keyword(s):  
B Cells ◽  
Autoimmune Encephalomyelitis ◽  
Regulatory B Cell ◽  
The Central Nervous System ◽  
Factor C ◽  
And Function ◽  
Human And Mouse ◽  
Experimental Autoimmune

AbstractB cells have essential functions in multiple sclerosis and in its mouse model, experimental autoimmune encephalomyelitis, both as drivers and suppressors of the disease. The suppressive effects are driven by a regulatory B cell (Breg) population that functions, primarily but not exclusively, via the production of IL-10. However, the mechanisms modulating IL-10-producing Breg abundance are poorly understood. Here we identify SLAMF5 for controlling IL-10+ Breg maintenance and function. In EAE, the deficiency of SLAMF5 in B cells causes accumulation of IL10+ Bregs in the central nervous system and periphery. Blocking SLAMF5 in vitro induces both human and mouse IL-10-producing Breg cells and increases their survival with a concomitant increase of a transcription factor, c-Maf. Finally, in vivo SLAMF5 blocking in EAE elevates IL-10+ Breg levels and ameliorates disease severity. Our results suggest that SLAMF5 is a negative moderator of IL-10+ Breg cells, and may serve as a therapeutic target in MS and other autoimmune diseases.

scholarly journals Toll-like receptor-9 stimulated plasmacytoid dendritic cell precursors suppress autoimmune neuroinflammation in a murine model of multiple sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hélène Letscher ◽  
Viviane A. Agbogan ◽  
Sarantis Korniotis ◽  
Pauline Gastineau ◽  
Emmanuel Tejerina ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Plasmacytoid Dendritic Cell ◽  
Toll Like Receptor ◽  
Hematopoietic Progenitors ◽  
Autoimmune Encephalomyelitis ◽  
Hematopoietic Precursor ◽  
Therapeutic Properties ◽  
Experimental Autoimmune

AbstractEarly innate education of hematopoietic progenitors within the bone marrow (BM) stably primes them for either trained immunity or instead immunoregulatory functions. We herein demonstrate that in vivo or in vitro activation within the BM via Toll-like receptor-9 generates a population of plasmacytoid dendritic cell (pDC) precursors (CpG-pre-pDCs) that, unlike pDC precursors isolated from PBS-incubated BM (PBS-pre-pDCs), are endowed with the capacity to halt progression of ongoing experimental autoimmune encephalomyelitis. CpG activation enhances the selective migration of pDC precursors to the inflamed spinal cord, induces their immediate production of TGF-β, and after migration, of enhanced levels of IL-27. CpG-pre-pDC derived TGF-β and IL-27 ensure protection at early and late phases of the disease, respectively. Spinal cords of CpG-pre-pDC-protected recipient mice display enhanced percentages of host-derived pDCs expressing TGF-β as well as an accumulation of IL-10 producing B cells and of CD11c+ CD11b+ dendritic cells. These results reveal that pDC precursors are conferred stable therapeutic properties by early innate activation within the BM. They further extend to the pDC lineage promising perspectives for cell therapy of autoimmune diseases with innate activated hematopoietic precursor cells.

scholarly journals Autonomous TNF is critical for in vivo monocyte survival in steady state and inflammation

2017 ◽  
Vol 214 (4) ◽  
pp. 905-917 ◽  
Author(s):  
Yochai Wolf ◽  
Anat Shemer ◽  
Michal Polonsky ◽  
Mor Gross ◽  
Alexander Mildner ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mononuclear Phagocytes ◽  
Autoimmune Encephalomyelitis ◽  
Wild Type Counterpart ◽  
And Function ◽  
Necrosis Factor ◽  
Experimental Autoimmune

Monocytes are circulating mononuclear phagocytes, poised to extravasate to sites of inflammation and differentiate into monocyte-derived macrophages and dendritic cells. Tumor necrosis factor (TNF) and its receptors are up-regulated during monopoiesis and expressed by circulating monocytes, as well as effector monocytes infiltrating certain sites of inflammation, such as the spinal cord, during experimental autoimmune encephalomyelitis (EAE). In this study, using competitive in vitro and in vivo assays, we show that monocytes deficient for TNF or TNF receptors are outcompeted by their wild-type counterpart. Moreover, monocyte-autonomous TNF is critical for the function of these cells, as TNF ablation in monocytes/macrophages, but not in microglia, delayed the onset of EAE in challenged animals and was associated with reduced acute spinal cord infiltration of Ly6Chi effector monocytes. Collectively, our data reveal a previously unappreciated critical cell-autonomous role of TNF on monocytes for their survival, maintenance, and function.

A shift in encephalitogenic T cell cytokine pattern is associated with suppression of EAE by intravenous immunoglobulins (IVIg)

1997 ◽  
Vol 3 (2) ◽  
pp. 153-156 ◽  
Author(s):  
Anastas Pashov ◽  
Blanche Bellon ◽  
Srini V Kaveri ◽  
Michel D Kazatchkine
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intravenous Immunoglobulins ◽  
Ivig Treatment ◽  
Autoimmune Encephalomyelitis ◽  
Proliferative Effect ◽  
Kinetics Of ◽  
Experimental Autoimmune

Pooled human polyspecific IgG preparations for intravenous use (IVIg) have been used in a number of antibody mediated autoimmune diseases and recently in some T cell mediated disorders including multiple sclerosis, birdshot retinopathy and rheumatoid arthritis. Furthermore, IVIg has been proven beneficial in the corresponding animal models, i.e. experimental autoimmune encephalomyelitis (EAE), experimental autoimmune uveoretinitis and adjuvant arthritis respectively. The exact mechanisms for IVIg adion in T cell mediated disorders are still poorly understood. There is evidence that IVIg treatment in vitro and in vivo decreases or changes the kinetics of the secretion by normal PBMC of a number of cytokines and anti-proliferative effect of IVIg on T cells in vitro and in vivo has also been reported. It remains unclear though to what extent the IVIg effects in T cell mediated autoimmunity are related only to non-specifc T cell suppression and whether it also reshapes the autoimmune T cell cytokine profile. In this study we demonstrate that IVIg protects against EAE and that this beneficial effed is associated with a decreased proli feration of T cells specific for the immunizing antigen. Moreover, we show that these antigen-specific cells produce low amount of Th /-type cytokines and transfer an attenuated EAE

scholarly journals Effect of Disease Stage on Clinical Outcome After Syngeneic Bone Marrow Transplantation for Relapsing Experimental Autoimmune Encephalomyelitis

Blood ◽  
1998 ◽  
Vol 91 (7) ◽  
pp. 2609-2616 ◽  
Author(s):  
Richard K. Burt ◽  
Josette Padilla ◽  
Wendy Smith Begolka ◽  
Mauro C. Dal Canto ◽  
Stephen D. Miller
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Chronic Phase ◽  
Autoimmune Encephalomyelitis ◽  
In Vitro Proliferation ◽  
Ifn Γ ◽  
Glial Scarring ◽  
Experimental Autoimmune

Abstract Relapsing experimental autoimmune encephalomyelitis (R-EAE) is an immune-mediated demyelinating central nervous system (CNS) disease. Myeloablation and syngeneic bone marrow transplantation (SBMT), when performed at the peak of acute disease (day 14), prevented glial scarring and ameliorated the disease severity. In contrast, when syngeneic BMT was performed late in chronic phase (day 78), significant glial scarring remained and the clinical severity did not differ significantly from that of the controls. After SBMT in either the acute or chronic phase of disease, the posttransplant immune system remained responsive to myelin epitopes as determined by in vitro proliferation and interferon-γ (IFN-γ) production. However, in mice undergoing SBMT, in vivo delayed-type hypersensitivity (DTH) responses were significantly decreased while IFN-γ RNA levels and inflammatory infiltrates within the CNS were slightly improved. We conclude that failure of SBMT to improve the clinical disease when performed in chronic phase may be due to preexisting glial scarring. We also conclude that in the absence of glial scarring and irreversible neuronal injury, in vivo DTH responses and histology are better predictors of clinical improvement than in vitro proliferation or IFN-γ cytokine production.

scholarly journals Thrombin Cleavage of Osteopontin Modulates Its Activities in Human CellsIn Vitroand Mouse Experimental Autoimmune EncephalomyelitisIn Vivo

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Elena Boggio ◽  
Chiara Dianzani ◽  
Casimiro Luca Gigliotti ◽  
Maria Felicia Soluri ◽  
Nausicaa Clemente ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Published Data ◽  
Autoimmune Encephalomyelitis ◽  
Thrombin Cleavage ◽  
The Central Nervous System ◽  
Potent Drug ◽  
Fine Tune ◽  
Experimental Autoimmune

Osteopontin is a proinflammatory cytokine and plays a pathogenetic role in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), by recruiting autoreactive T cells into the central nervous system. Osteopontin functions are modulated by thrombin cleavage generating N- and C-terminal fragment, whose individual roles are only partly known. Published data are difficult to compare since they have been obtained with heterogeneous approaches. Interestingly, thrombin cleavage of osteopontin unmasks a cryptic domain of interaction withα4β1integrin that is the main adhesion molecule involved in lymphocyte transmigration to the brain and is the target for natalizumab, the most potent drug preventing relapses. We produced recombinant osteopontin and its N- and C-terminal fragments in an eukaryotic system in order to allow their posttranslational modifications. We investigated,in vitro,their effect on human cells andin vivoin EAE. We found that the osteopontin cleavage plays a key role in the function of this cytokine and that the two fragments exert distinct effects bothin vitroandin vivo. These findings suggest that drugs targeting each fragment may be used to fine-tune the pathological effects of osteopontin in several diseases.

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