Ageing impairs the regenerative capacity of regulatory T cells in mouse central nervous system remyelination.

Myelin regeneration (remyelination) is essential to prevent neurodegeneration in demyelinating diseases such as Multiple Sclerosis, however, its efficiency declines with age. Regulatory T cells (Treg) recently emerged as critical players in tissue regeneration, including remyelination. However, the effect of ageing on Treg-mediated regenerative processes is poorly understood.

Blockade of Proteinase-Activated Receptor 2 (PAR2) Attenuates Neuroinflammation in Experimental Autoimmune Encephalomyelitis.

Proteinase-activated receptor-2 (PAR2), which modulates inflammatory responses, is elevated in the central nervous system in multiple sclerosis (MS) and in its murine model, experimental autoimmune encephalomyelitis (EAE). In PAR2-null mice, disease severity of EAE is markedly diminished. We therefore tested whether inhibiting PAR2 activation in vivo might be a viable strategy for the treatment of MS.

Glial aging and its impact on central nervous system myelin regeneration.

Aging is a major risk factor for several neurodegenerative diseases and is associated with cognitive decline. In addition to affecting neuronal function, the aging process significantly affects the functional phenotype of the glial cell compartment, comprising oligodendrocyte lineage cells, astrocytes, and microglia. These changes result in a more inflammatory microenvironment, resulting in a condition that is favorable for neuron and synapse loss.

Detecting monocyte trafficking in an animal model of glioblastoma using R* and quantitative susceptibility mapping.

Background: The role of tumor-associated macrophages (TAMs) in glioblastoma (GBM) disease progression has received increasing attention. Recent advances have shown that TAMs can be re-programmed to exert a pro-inflammatory, anti-tumor effect to control GBMs. However, imaging methods capable of differentiating tumor progression from immunotherapy treatment effects have been lacking, making timely assessment of treatment response difficult.

A metric learning method for estimating myelin content based on T2-weighted MRI from a de- and re-myelination model of multiple sclerosis.

Myelin plays a critical role in the pathogenesis of neurological disorders but is difficult to characterize in vivo using standard analysis methods. Our goal was to develop a novel analytical framework for estimating myelin content using T2-weighted magnetic resonance imaging (MRI) based on a de- and re-myelination model of multiple sclerosis. We examined 18 mice with lysolecithin induced demyelination and spontaneous remyelination in the ventral white matter of thoracic spinal cord.

Harnessing the Benefits of Neuroinflammation: Generation of Macrophages/Microglia with Prominent Remyelinating Properties.

Excessive inflammation within the CNS is injurious, but an immune response is also required for regeneration. Macrophages and microglia adopt different properties depending on their microenvironment, and exposure to IL4 and IL13 has been used to elicit repair. Unexpectedly, while LPS-exposed macrophages and microglia killed neural cells in culture, the addition of LPS to IL4/IL13-treated macrophages and microglia profoundly elevated IL10, repair metabolites, heparin binding epidermal growth factor trophic factor, antioxidants, and matrix-remodeling proteases.

Microglia Diversity in Health and Multiple Sclerosis.

Multiple Sclerosis (MS) is a neurodegenerative disease characterized by multiple focal lesions, ongoing demyelination and, for most people, a lack of remyelination. MS lesions are enriched with monocyte-derived macrophages and brain-resident microglia that, together, are likely responsible for much of the immune-mediated neurotoxicity. However, microglia and macrophage also have documented neuroprotective and regenerative roles, suggesting a potential diversity in their functions.

Aging-Exacerbated Acute Axon and Myelin Injury Is Associated with Microglia-Derived Reactive Oxygen Species and Is Alleviated by the Generic Medication Indapamide.

Age is a critical risk factor for many neurologic conditions, including progressive multiple sclerosis. Yet the mechanisms underlying the relationship are unknown. Using lysolecithin-induced demyelinating injury to the mouse spinal cord, we characterized the acute lesion and investigated the mechanisms of increased myelin and axon damage with age.

The glycosyltransferase EXTL2 promotes proteoglycan deposition and injurious neuroinflammation following demyelination.

Background: Chondroitin sulfate proteoglycans (CSPGs) are potent inhibitors of axonal regrowth and remyelination. More recently, they have also been highlighted as a modulator of macrophage infiltration into the central nervous system in experimental autoimmune encephalomyelitis, an inflammatory model of multiple sclerosis.

Methods: We interrogated results from single nucleotide polymorphisms (SNPs) lying in or close to genes regulating CSPG metabolism in the summary results from two publicly available systematic studies of multiple sclerosis (MS) genetics.

The Role of Astrocytes in Remyelination.

Remyelination is the regeneration of myelin sheaths following demyelination. This regenerative process is critical for the re-establishment of axonal conduction velocity and metabolic support to the axons. Successful remyelination in the CNS generally depends on the activation, proliferation, and differentiation of oligodendrocyte progenitor cells (OPCs).

Control of brain tumor growth by reactivating myeloid cells with niacin.

Glioblastomas are generally incurable partly because monocytes, macrophages, and microglia in afflicted patients do not function in an antitumor capacity. Medications that reactivate these macrophages/microglia, as well as circulating monocytes that become macrophages, could thus be useful to treat glioblastoma. We have discovered that niacin (vitamin B3) is a potential stimulator of these inefficient myeloid cells.

Correction to: Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system.

The article Niacin‑mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system, written by Khalil S. Rawji, Adam M.H.

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes.

Myeloid cells that infiltrate into brain tumors are deactivated or exploited by the tumor cells. We previously demonstrated that compromised microglia, monocytes, and macrophages in malignant gliomas could be reactivated by amphotericin-B to contain the growth of brain tumorinitiating cells (BTICs). We identified meclocycline as another activator of microglia, so we sought to test whether its better-tolerated derivative, demeclocycline, also stimulates monocytes to restrict BTIC growth.

Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system.

Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris.

Microglia response following acute demyelination is heterogeneous and limits infiltrating macrophage dispersion.

Microglia and infiltrating macrophages are thought to orchestrate the central nervous system (CNS) response to injury; however, the similarities between these cells make it challenging to distinguish their relative contributions. We genetically labeled microglia and CNS-associated macrophages to distinguish them from infiltrating macrophages. Using single-cell RNA sequencing, we describe multiple microglia activation states, one of which was enriched for interferon associated signaling.

Central Nervous System Remyelination: Roles of Glia and Innate Immune Cells.

In diseases such as multiple sclerosis (MS), inflammation can injure the myelin sheath that surrounds axons, a process known as demyelination. The spontaneous regeneration of myelin, called remyelination, is associated with restoration of function and prevention of axonal degeneration. Boosting remyelination with therapeutic intervention is a promising new approach that is currently being tested in several clinical trials.

Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells.

The age-related failure to produce oligodendrocytes from oligodendrocyte progenitor cells (OPCs) is associated with irreversible neurodegeneration in multiple sclerosis (MS). Consequently, regenerative approaches have significant potential for treating chronic demyelinating diseases. Here, we show that the differentiation potential of adult rodent OPCs decreases with age.

Targeting the Chondroitin Sulfate Proteoglycans: Evaluating Fluorinated Glucosamines and Xylosides in Screens Pertinent to Multiple Sclerosis.

Chondroitin sulfate proteoglycans (CSPGs) are upregulated in insults to the central nervous system, including multiple sclerosis (MS), an inflammatory demyelinating condition of the central nervous system. CSPGs appear to be detrimental in MS, as they enhance immune responses and act as barriers to oligodendrocyte differentiation and thus remyelination. Despite their deleterious roles, strategies to selectively reduce CSPG production are lacking.

Enhanced glycolytic metabolism supports transmigration of brain-infiltrating macrophages in multiple sclerosis.

The migration of leukocytes into the CNS drives the neuropathology of multiple sclerosis (MS). This penetration likely utilizes energy resources that remain to be defined. Using the experimental autoimmune encephalomyelitis (EAE) model of MS, we determined that macrophages within the perivascular cuff of post-capillary venules are highly glycolytic as manifested by strong expression of lactate dehydrogenase A (LDHA) that converts pyruvate to lactate.

The benefits of neuroinflammation for the repair of the injured central nervous system.

Inflammation of the nervous system (neuroinflammation) is now recognized as a hallmark of virtually all neurological disorders. In neuroinflammatory conditions such as multiple sclerosis, there is prominent infiltration and a long-lasting representation of various leukocyte subsets in the central nervous system (CNS) parenchyma. Even in classic neurodegenerative disorders, where such immense inflammatory infiltrates are absent, there is still evidence of activated CNS-intrinsic microglia.

Microglia induces Gas1 expression in human brain tumor-initiating cells to reduce tumorigenecity.

We reported previously that microglia decreased the growth of human brain tumor-initiating cells (BTICs). Through microarray analyses of BTICs exposed in vitro to microglia, we found the induction of several genes ascribed to have roles in cell cycle arrest, reduced cell proliferation and differentiation. Herein, we tested the hypothesis that one of these genes, growth arrest specific 1 (Gas1), is a novel growth reduction factor that is induced in BTICs by microglia.

Brain tumor-initiating cells export tenascin-C associated with exosomes to suppress T cell activity.

The dismal prognosis of glioblastoma is attributed in part to the existence of stem-like brain tumor-initiating cells (BTICs) that are highly radio- and chemo-resistant. New approaches such as therapies that reprogram compromised immune cells against BTICs are needed. Effective immunotherapies in glioblastoma, however, remain elusive unless the mechanisms of immunosuppression by the tumor are better understood.