scholarly journals Thyroid hormone and thyromimetics inhibit myelin and axonal degeneration and oligodendrocyte loss in EAE

2020 ◽  
Author(s):  
P Chaudhary ◽  
GH Marracci ◽  
E Calkins ◽  
E Pocius ◽  
AL Bensen ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Axonal Degeneration ◽  
List Type ◽  
Protective Effects ◽  
Autoimmune Encephalomyelitis ◽  
Thyroid Receptor ◽  
Oligodendrocyte Precursor ◽  
Receptor Beta ◽  
Experimental Autoimmune ◽  
Degenerating Axons

AbstractWe have previously demonstrated that thyromimetics stimulate oligodendrocyte precursor cell differentiation and promote remyelination in murine demyelination models. We investigated whether a thyroid receptor-beta selective thyromimetic, sobetirome (Sob), and its CNS-targeted prodrug, Sob-AM2, could prevent myelin and axonal degeneration in experimental autoimmune encephalomyelitis (EAE). Compared to controls, EAE mice receiving triiodothyronine (T3, 0.4mg/kg), Sob (5mg/kg) or Sob-AM2 (5mg/kg) had reduced clinical disease and, within the spinal cord, less tissue damage, more normally myelinated axons, fewer degenerating axons and more oligodendrocytes. T3 and Sob also protected cultured oligodendrocytes against cell death. Thyromimetics thus might protect against oligodendrocyte death, demyelination and axonal degeneration as well as stimulate remyelination in multiple sclerosis.HighlightsThyroid hormone, the thyromimetic Sob and its CNS penetrating prodrug, Sob-AM2, reduce disease severity, reduce myelin and axonal degeneration and protect oligodendrocytes in EAE.The benefits of Sob and Sob-AM2 may be via direct protective effects on oligodendrocytes and reduction in activity of microglia/macrophages.

Thyroid receptor ligands. Part 4: 4′-amido bioisosteric ligands selective for the thyroid hormone receptor beta

2006 ◽  
Vol 16 (4) ◽  
pp. 884-886 ◽  
Author(s):  
Yi-Lin Li ◽  
Chris Litten ◽  
Konrad F. Koehler ◽  
Karin Mellström ◽  
Neeraj Garg ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Receptor Ligands ◽  
Thyroid Receptor ◽  
Receptor Beta

scholarly journals Deletion of arginase 2 attenuates neuroinflammation in an experimental model of optic neuritis

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0247901
Author(s):  
Amritha A. Candadai ◽  
Fang Liu ◽  
Abdelrahman Y. Fouda ◽  
Moaddey Alfarhan ◽  
Chithra D. Palani ◽  
...  
Keyword(s):  
Optic Neuritis ◽  
Experimental Model ◽  
Axonal Degeneration ◽  
Wild Type ◽  
Autoimmune Encephalomyelitis ◽  
Optic Nerves ◽  
Clinical Presentations ◽  
Retinal Neurodegeneration ◽  
The Impact ◽  
Experimental Autoimmune

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.

scholarly journals Dectin-1 limits central nervous system autoimmunity through a non-canonical pathway

2020 ◽  
Author(s):  
M. Elizabeth Deerhake ◽  
Keiko Danzaki ◽  
Makoto Inoue ◽  
Emre D. Cardakli ◽  
Toshiaki Nonaka ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Myeloid Cells ◽  
Oncostatin M ◽  
List Type ◽  
Autoimmune Encephalomyelitis ◽  
Protective Function ◽  
Lectin Receptor ◽  
Neurologic Disorders ◽  
Cns Autoimmunity ◽  
Experimental Autoimmune

ABSTRACTPathologic roles for innate immunity in neurologic disorders are well-described, but protective aspects of the immune response are less understood. Dectin-1, a C-type lectin receptor (CLR), is largely known to induce inflammation. However, we found that Dectin-1 is protective in experimental autoimmune encephalomyelitis (EAE), while its canonical signaling mediator, Card9, promotes the disease. Notably, Dectin-1 does not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Myeloid cells mediate the protective function of Dectin-1 in EAE and upregulate gene expression of neuroprotective molecules, including Oncostatin M (Osm) through a non-canonical Card9-independent pathway, mediated by NFAT. Furthermore, we found that the Osm receptor (OsmR) functions specifically in astrocytes to reduce EAE severity. Our study revealed a new mechanism of protective myeloid-astrocyte crosstalk regulated by a non-canonical Dectin-1 pathway and identifies novel therapeutic targets for CNS autoimmunity.Graphical AbstractDectin-1 is a protective C-type lectin receptor (CLR) in experimental autoimmune encephalomyelitis (EAE)Dectin-1 promotes expression of Osm, a neuroprotective IL-6 family cytokine, in myeloid cellsOsmR signaling in astrocytes limits EAE progression and promotes remissionNon-canonical Card9-independent signaling drives a distinct Dectin-1-mediated transcriptional program to induce expression of Osm and other factors with protective or anti-inflammatory functions

scholarly journals MS CD49d+CD154+ Lymphocytes Reprogram Oligodendrocytes into Immune Reactive Cells Affecting CNS Regeneration

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1508 ◽  
Author(s):  
Paweł Piatek ◽  
Magdalena Namiecinska ◽  
Małgorzata Domowicz ◽  
Patrycja Przygodzka ◽  
Marek Wieczorek ◽  
...  
Keyword(s):  
Basic Protein ◽  
Proteolipid Protein ◽  
Critical Aspect ◽  
Autoimmune Encephalomyelitis ◽  
Circulating Lymphocytes ◽  
Oligodendrocyte Precursor ◽  
Cellular Pathways ◽  
Cytokine Synthesis ◽  
Experimental Autoimmune

The critical aspect in multiple sclerosis (MS) progression involves insufficient regeneration of CNS resulting from deficient myelin synthesis by newly generated oligodendrocytes (OLs). Although many studies have focused on the role of autoreactive lymphocytes in the inflammatory-induced axonal loss, the problem of insufficient remyelination and disease progression is still unsolved. To determine the effect of myelin-specific lymphocytes on OL function in MS patients and in a mouse model of MS, we cultured myelin induced MS CD49d+CD154+ circulating lymphocytes as well as Experimental Autoimmune Encephalomyelitis (EAE) mouse brain-derived T and memory B cells with maturing oligodendrocyte precursor cells (OPCs). We found that myelin-specific CD49d+CD154+ lymphocytes affected OPC maturation toward formation of immune reactive OLs. Newly generated OLs were characterized by imbalanced myelin basic protein (MBP) and proteolipid protein (PLP) production as well as proinflammatory chemokine/cytokine synthesis. The analysis of cellular pathways responsible for OL reprogramming revealed that CD49d+CD154+ lymphocytes affected miRNA synthesis by dysregulation of polymerase II activity. miR-665 and ELL3 turned out to be the main targets of MS myelin-specific lymphocytes. Neutralization of high intracellular miR-665 concentration restored miRNA and MBP/PLP synthesis. Together, these data point to new targets for therapeutic intervention promoting CNS remyelination.

scholarly journals A rare mutation of thyroid hormone receptor beta gene in thyroid hormone resistance syndrome

2021 ◽  
Vol 2021 ◽  
Author(s):  
Michela Del Prete ◽  
Fabrizio Muratori ◽  
Irene Campi ◽  
Gianleone Di Sacco ◽  
Federico Vignati ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Genetic Test ◽  
List Type ◽  
Thyroid Function Tests ◽  
Resistance To Thyroid Hormone ◽  
Hereditary Syndrome ◽  
Serum Tsh ◽  
Receptor Beta ◽  
Tsh Levels

Summary Resistance to thyroid hormone (RTH) is a rare hereditary syndrome with impaired sensitivity to thyroid hormones (TH) and reduced intracellular action of triiodothyronine (T3) caused by genetic variants of TH receptor beta (TRB) or alpha (TRA). RTH type beta (RTHβ) due to dominant negative variants in the TRB gene usually occurs with persistent elevation of circulating free TH, non-suppressed serum TSH levels responding to a thyrotropin-releasing hormone (TRH) test, an absence of typical symptoms of hyperthyroidism and goiter. Here, we present a rare variant in the TRB gene reported for the first time in an Italian patient with generalized RTHβ syndrome. The patient showed elevated TH, with non-suppressed TSH levels and underwent thyroid surgery two different times for multinodular goiter. The genetic test showed a heterozygous mutation in exon 9 of the TRB gene resulting in the replacement of threonine (ACG) with methionine (ATG) at codon 310 (p.M310T). RTHβ syndrome should be considered in patients with elevated TH, non-suppressed TSH levels and goiter. Learning points Resistance to thyroid hormone (RTH) is a rare autosomal dominant hereditary syndrome with impaired tissue responsiveness to thyroid hormones (TH). Diagnosis of RTH is usually based on the clinical finding of discrepant thyroid function tests and confirmed by a genetic test. RTH is a rare condition that must be considered for the management of patients with goiter, elevation of TH and non-suppressed serum TSH levels in order to avoid unnecessary treatments.

scholarly journals The Benefits and Detriments of Macrophages/Microglia in Models of Multiple Sclerosis

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Khalil S. Rawji ◽  
V. Wee Yong
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cells ◽  
Neurotrophic Factors ◽  
Neurological Diseases ◽  
Oligodendrocyte Precursor Cells ◽  
Activated Macrophages ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Oligodendrocyte Precursor ◽  
Experimental Autoimmune

The central nervous system (CNS) is immune privileged with access to leukocytes being limited. In several neurological diseases, however, infiltration of immune cells from the periphery into the CNS is largely observed and accounts for the increased representation of macrophages within the CNS. In addition to extensive leukocyte infiltration, the activation of microglia is frequently observed. The functions of activated macrophages/microglia within the CNS are complex. In three animal models of multiple sclerosis (MS), namely, experimental autoimmune encephalomyelitis (EAE) and cuprizone- and lysolecithin-induced demyelination, there have been many reported detrimental roles associated with the involvement of macrophages and microglia. Such detriments include toxicity to neurons and oligodendrocyte precursor cells, release of proteases, release of inflammatory cytokines and free radicals, and recruitment and reactivation of T lymphocytes in the CNS. Many studies, however, have also reported beneficial roles of macrophages/microglia, including axon regenerative roles, assistance in promoting remyelination, clearance of inhibitory myelin debris, and the release of neurotrophic factors. This review will discuss the evidence supporting the detrimental and beneficial aspects of macrophages/microglia in models of MS, provide a discussion of the mechanisms underlying the dichotomous roles, and describe a few therapies in clinical use in MS that impinge on the activity of macrophages/microglia.

scholarly journals Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

2005 ◽  
Vol 185 (2) ◽  
pp. 243-252 ◽  
Author(s):  
M Merle Elloso ◽  
Kristen Phiel ◽  
Ruth A Henderson ◽  
Heather A Harris ◽  
Steven J Adelman
Keyword(s):  
Multiple Sclerosis ◽  
Estrogen Receptor ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Responses ◽  
Clinical Symptoms ◽  
Protective Effects ◽  
Autoimmune Encephalomyelitis ◽  
Selective Agonist ◽  
Selective Ligands ◽  
Experimental Autoimmune

Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ERα and ERβ. The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17β-estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ERα-selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ERβ-selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139–151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ERβ agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ERα-selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.

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