scholarly journals Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration

2012 ◽  
Vol 209 (3) ◽  
pp. 521-535 ◽  
Author(s):  
Emanuela Colombo ◽  
Chiara Cordiglieri ◽  
Giorgia Melli ◽  
Jia Newcombe ◽  
Markus Krumbholz ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
White Matter Lesions ◽  
Neurotrophin Receptor ◽  
Autoimmune Encephalomyelitis ◽  
Vitro Assay ◽  
Neurodegenerative Process ◽  
The Central Nervous System ◽  
And Function ◽  
Experimental Autoimmune

Neurotrophin growth factors support neuronal survival and function. In this study, we show that the expression of the neurotrophin receptor TrkB is induced on astrocytes in white matter lesions in multiple sclerosis (MS) patients and mice with experimental autoimmune encephalomyelitis (EAE). Surprisingly, mice lacking TrkB specifically in astrocytes were protected from EAE-induced neurodegeneration. In an in vitro assay, astrocytes stimulated with the TrkB agonist brain-derived neurotrophic factor (BDNF) released nitric oxide (NO), and conditioned medium from activated astrocytes had detrimental effects on the morphology and survival of neurons. This neurodegenerative process was amplified by NO produced by neurons. NO synthesis in the central nervous system during EAE depended on astrocyte TrkB. Together, these findings suggest that TrkB expression on astrocytes may represent a new target for neuroprotective therapies in MS.

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 Amino acid sequence of the encephalitogenic basic protein from human myelin

1971 ◽  
Vol 123 (1) ◽  
pp. 57-67 ◽  
Author(s):  
P. R. Carnegie
Keyword(s):  
Amino Acids ◽  
Central Nervous System ◽  
Nervous System ◽  
Amino Acid ◽  
Basic Protein ◽  
Structure And Function ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
And Function ◽  
Experimental Autoimmune

Myelin from the central nervous system contains an unusual basic protein, which can induce experimental autoimmune encephalomyelitis. The basic protein from human brain was digested with trypsin and other enzymes and the sequence of the 170 amino acids was determined. The localization of the encephalitogenic determinants was described. Possible roles for the protein in the structure and function of myelin are discussed.

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.

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.

scholarly journals IFP35 family proteins promote neuroinflammation and multiple sclerosis

2021 ◽  
Vol 118 (32) ◽  
pp. e2102642118
Author(s):  
Xizhong Jing ◽  
Yongjie Yao ◽  
Danning Wu ◽  
Hao Hong ◽  
Xu Feng ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Immune Cells ◽  
Neutralizing Antibodies ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Multiple Cells ◽  
Excessive Activation ◽  
Experimental Autoimmune

Excessive activation of T cells and microglia represents a hallmark of the pathogenesis of human multiple sclerosis (MS). However, the regulatory molecules overactivating these immune cells remain to be identified. Previously, we reported that extracellular IFP35 family proteins, including IFP35 and NMI, activated macrophages as proinflammatory molecules in the periphery. Here, we investigated their functions in the process of neuroinflammation both in the central nervous system (CNS) and the periphery. Our analysis of clinical transcriptomic data showed that expression of IFP35 family proteins was up-regulated in patients with MS. Additional in vitro studies demonstrated that IFP35 and NMI were released by multiple cells. IFP35 and NMI subsequently triggered nuclear factor kappa B–dependent activation of microglia via the TLR4 pathway. Importantly, we showed that both IFP35 and NMI activated dendritic cells and promoted naïve T cell differentiation into Th1 and Th17 cells. Nmi−/−, Ifp35−/−, or administration of neutralizing antibodies against IFP35 alleviated the immune cells’ infiltration and demyelination in the CNS, thus reducing the severity of experimental autoimmune encephalomyelitis. Together, our findings reveal a hitherto unknown mechanism by which IFP35 family proteins facilitate overactivation of both T cells and microglia and propose avenues to study the pathogenesis of MS.

scholarly journals A T cell-intrinsic function for NF-κB RelB in experimental autoimmune encephalomyelitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Guilhem Lalle ◽  
Raphaëlle Lautraite ◽  
Allison Voisin ◽  
Julie Twardowski ◽  
Pierre Stéphan ◽  
...  
Keyword(s):  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Clinical Severity ◽  
Autoimmune Encephalomyelitis ◽  
Gm Csf ◽  
Macrophage Colony ◽  
Nf Kappab ◽  
And Function ◽  
Experimental Autoimmune

AbstractNF-kappaB (NF-κB) is a family of transcription factors with pleiotropic functions in immune responses. The alternative NF-κB pathway that leads to the activation of RelB and NF-κB2, was previously associated with the activation and function of T cells, though the exact contribution of these NF-κB subunits remains unclear. Here, using mice carrying conditional ablation of RelB in T cells, we evaluated its role in the development of conventional CD4+ T (Tconv) cells and their function in autoimmune diseases. RelB was largely dispensable for Tconv cell homeostasis, activation and proliferation, and for their polarization toward different flavors of Thelper cells in vitro. Moreover, ablation of RelB had no impact on the capacity of Tconv cells to induce autoimmune colitis. Conversely, clinical severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS) was significantly reduced in mice with RelB-deficient T cells. This was associated with impaired expression of granulocyte–macrophage colony-stimulating factor (GM-CSF) specifically in the central nervous system. Our data reveal a discrete role for RelB in the pathogenic function of Tconv cells during EAE, and highlight this transcription factor as a putative therapeutic target in MS.

scholarly journals Multiple Sclerosis CD49d+CD154+ As Myelin-Specific Lymphocytes Induced During Remyelination

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 15
Author(s):  
Paweł Piatek ◽  
Magdalena Namiecinska ◽  
Małgorzata Domowicz ◽  
Marek Wieczorek ◽  
Sylwia Michlewska ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cumulative Effect ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Cns Demyelination ◽  
The Brain ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) mediated by autoreactive lymphocytes. The role of autoreactive lymphocytes in the CNS demyelination is well described, whereas very little is known about their role in remyelination during MS remission. In this study, we identified a new subpopulation of myelin-specific CD49d+CD154+ lymphocytes presented in the peripheral blood of MS patients during remission, that proliferated in vitro in response to myelin peptides. These lymphocytes possessed the unique ability to migrate towards maturing oligodendrocyte precursor cells (OPCs) and synthetize proinflammatory chemokines/cytokines. The co-culture of maturing OPCs with myelin-specific CD49d+CD154+ lymphocytes was characterized by the increase in proinflammatory chemokine/cytokine secretion that was not only a result of their cumulative effect of what OPCs and CD49d+CD154+ lymphocytes produced alone. Moreover, maturing OPCs exposed to exogenous myelin peptides managed to induce CD40-CD154-dependent CD49d+CD154+ lymphocyte proliferation. We confirmed, in vivo, the presence of CD49d+CD154+ cells close to maturating OPCs and remyelinating plaque during disease remission in the MS mouse model (C57Bl/6 mice immunized with MOG35-55) by immunohistochemistry. Three weeks after an acute phase of experimental autoimmune encephalomyelitis, CD49d+/CD154+ cells were found to be co-localized with O4+ cells (oligodendrocyte progenitors) in the areas of remyelination identified by myelin basic protein (MBP) labelling. These data suggested that myelin-specific CD49d+CD154+ lymphocytes present in the brain can interfere with remyelination mediated by oligodendrocytes probably as a result of establishing proinflammatory environment.

scholarly journals CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity

2011 ◽  
Vol 208 (2) ◽  
pp. 327-339 ◽  
Author(s):  
Lillian Cruz-Orengo ◽  
David W. Holman ◽  
Denise Dorsey ◽  
Liang Zhou ◽  
Penglie Zhang ◽  
...  
Keyword(s):  
Interferon Γ ◽  
Interleukin 17 ◽  
Leukocyte Infiltration ◽  
Brain Endothelial Cells ◽  
Autoimmune Encephalomyelitis ◽  
Inflammatory Infiltration ◽  
Endothelial Barriers ◽  
The Central Nervous System ◽  
Experimental Autoimmune

Loss of CXCL12, a leukocyte localizing cue, from abluminal surfaces of the blood–brain barrier occurs in multiple sclerosis (MS) lesions. However, the mechanisms and consequences of reduced abluminal CXCL12 abundance remain unclear. Here, we show that activation of CXCR7, which scavenges CXCL12, is essential for leukocyte entry via endothelial barriers into the central nervous system (CNS) parenchyma during experimental autoimmune encephalomyelitis (EAE), a model for MS. CXCR7 expression on endothelial barriers increased during EAE at sites of inflammatory infiltration. Treatment with a CXCR7 antagonist ameliorated EAE, reduced leukocyte infiltration into the CNS parenchyma and parenchymal VCAM-1 expression, and increased abluminal levels of CXCL12. Interleukin 17 and interleukin 1β increased, whereas interferon-γ decreased, CXCR7 expression on and CXCL12 internalization in primary brain endothelial cells in vitro. These findings identify molecular requirements for the transvascular entry of leukocytes into the CNS and suggest that CXCR7 blockade may have therapeutic utility for the treatment of MS.

scholarly journals SLAMF9 regulates pDC homeostasis and function in health and disease

2019 ◽  
Vol 116 (33) ◽  
pp. 16489-16496 ◽  
Author(s):  
Lital Sever ◽  
Lihi Radomir ◽  
Kristin Stirm ◽  
Anna Wiener ◽  
Nofar Schottlender ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Adaptive Immune Response ◽  
Response Analysis ◽  
Type I ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Health And Disease ◽  
And Function ◽  
Experimental Autoimmune

SLAMF9 belongs to the conserved lymphocytic activation molecule family (SLAMF). Unlike other SLAMs, which have been extensively studied, the role of SLAMF9 in the immune system remained mostly unexplored. By generating CRISPR/Cas9 SLAMF9 knockout mice, we analyzed the role of this receptor in plasmacytoid dendritic cells (pDCs), which preferentially express the SLAMF9 transcript and protein. These cells display a unique capacity to produce type I IFN and bridge between innate and adaptive immune response. Analysis of pDCs in SLAMF9−/− mice revealed an increase of immature pDCs in the bone marrow and enhanced accumulation of pDCs in the lymph nodes. In the periphery, SLAMF9 deficiency resulted in lower levels of the transcription factor SpiB, elevation of pDC survival, and attenuated IFN-α and TNF-α production. To define the role of SLAMF9 during inflammation, pDCs lacking SLAMF9 were followed during induced experimental autoimmune encephalomyelitis. SLAMF9−/− mice demonstrated attenuated disease and delayed onset, accompanied by a prominent increase of immature pDCs in the lymph node, with a reduced costimulatory potential and enhanced infiltration of pDCs into the central nervous system. These results suggest the crucial role of SLAMF9 in pDC differentiation, homeostasis, and function in the steady state and during experimental autoimmune encephalomyelitis.

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