PDGFRα-positive cell-derived TIMP-1 modulates adaptive immune responses to influenza A viral infection.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a physiologic inhibitor of the matrix metalloproteinases (MMPs), but little is known about the role of TIMP-1 in regulating the pathogenesis of influenza A virus (IAV) infection. Here, we performed both in vivo and in vitro experiments to investigate the regulation and function of TIMP-1 during IAV infection. Specifically, plasma levels of TIMP-1 are significantly increased in human subjects and wild-type (WT) mice infected with 2009 H1N1 IAV compared with levels in uninfected controls.

TIMP1 Mediates Astrocyte-Dependent Local Immunosuppression in Brain Metastasis Acting on Infiltrating CD8+ T Cells.

Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here, we dissect the heterogeneity in metastasis-associated astrocytes using single-cell RNA sequencing and report a population that blocks the antitumoral activity of infiltrating T cells. This protumoral activity is mediated by the secretion of tissue inhibitor of metalloproteinase-1 (TIMP1) from a cluster of pSTAT3+ astrocytes that acts on CD63+ CD8+ T cells to modulate their function.

C1ql1 expression in oligodendrocyte progenitor cells promotes oligodendrocyte differentiation.

Myelinating oligodendrocytes arise from the stepwise differentiation of oligodendrocyte progenitor cells (OPCs). Approximately 5% of all adult brain cells are OPCs. Why would a mature brain need such a large number of OPCs? New myelination is possibly required for higher-order functions such as cognition and learning.

Astrocytic TIMP-1 regulates production of Anastellin, an inhibitor of oligodendrocyte differentiation and FTY720 responses.

Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. Astrocytes that lack expression of do not support rat oligodendrocyte progenitor cell (rOPC) differentiation, and adult global knockout () mice do not efficiently remyelinate following a demyelinating injury.

Emerging Role of Astrocyte-Derived Extracellular Vesicles as Active Participants in CNS Neuroimmune Responses.

Astrocyte-derived extracellular vesicles (ADEVs) have garnered attention as a fundamental mechanism of intercellular communication in health and disease. In the context of neurological diseases, for which prodromal diagnosis would be advantageous, ADEVs are also being explored for their potential utility as biomarkers. In this review, we provide the current state of data supporting our understanding on the manifold roles of ADEVs in several common neurological disorders.

CD8+ T cell depletion prevents neuropathology in a mouse model of globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD) or Krabbe's disease is a fatal genetic demyelinating disease of the central nervous system caused by loss-of-function mutations in the galactosylceramidase (galc) gene. While the metabolic basis for disease is known, the understanding of how this results in neuropathology is not well understood. Herein, we report that the rapid and protracted elevation of CD8+ cytotoxic T lymphocytes occurs coincident with clinical disease in a mouse model of GLD.

Astrocytic TIMP-1 regulates production of Anastellin, a novel inhibitor of oligodendrocyte differentiation and FTY720 responses.

Unlabelled: Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. We have previously demonstrated that murine astrocytes that lack expression of do not support rat oligodendrocyte progenitor cell (rOPC) differentiation, and adult global knockout ( ) mice do not efficiently remyelinate following a demyelinating injury.

Glia as antigen-presenting cells in the central nervous system.

The contribution of the cells within the central nervous system (CNS) toward adaptive immune responses is emerging and incompletely understood. Recent findings indicate important functional interactions between T-cells and glial cells within the CNS that may contribute to disease and neuropathology through antigen presentation. Although glia are not classically considered antigen-presenting cell (APC) types, there is growing evidence indicating that glial antigen presentation plays an important role in several neurological diseases.

Cuprizone-mediated demyelination reversibly degrades voiding behavior in mice while sparing brainstem reflex.

Multiple sclerosis (MS) is a chronic, progressively debilitating demyelinating disease of the central nervous system (CNS). Nearly 80% of MS patients experience lower urinary tract dysfunction early in their diagnosis. This significantly affects the quality of life, and in latter stages of disease is a leading cause of hospitalization.

The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination.

HMGB1 is a highly conserved, ubiquitous protein in eukaryotic cells. HMGB1 is normally localized to the nucleus, where it acts as a chromatin associated non-histone binding protein. In contrast, extracellular HMGB1 is an alarmin released by stressed cells to act as a danger associated molecular pattern (DAMP).

Lipidomic analysis identifies age-disease-related changes and potential new biomarkers in brain-derived extracellular vesicles from metachromatic leukodystrophy mice.

Background: Recent findings show that extracellular vesicle constituents can exert short- and long-range biological effects on neighboring cells in the brain, opening an exciting avenue for investigation in the field of neurodegenerative diseases. Although it is well documented that extracellular vesicles contain many lipids and are enriched in sphingomyelin, cholesterol, phosphatidylserines and phosphatidylinositols, no reports have addressed the lipidomic profile of brain derived EVs in the context of Metachromatic Leukodystrophy, a lysosomal storage disease with established metabolic alterations in sulfatides.

Methods: In this study, we isolated and characterized the lipid content of brain-derived EVs using the arylsulfatase A knockout mouse as a model of the human condition.

The Pathogenic Sphingolipid Psychosine is Secreted in Extracellular Vesicles in the Brain of a Mouse Model of Krabbe Disease.

Psychosine exerts most of its toxic effects by altering membrane dynamics with increased shedding of extracellular vesicles (EVs). In this study, we discovered that a fraction of psychosine produced in the brain of the Twitcher mouse, a model for Krabbe disease, is associated with secreted EVs. We evaluated the effects of attenuating EV secretion in the Twitcher brain by depleting ceramide production with an inhibitor of neutral sphingomyelinase 2, GW4869.

Therapeutic opportunities for targeting cellular senescence in progressive multiple sclerosis.

Recent studies have implicated cellular senescence as a disease-related process linked to progressive forms of multiple sclerosis (MS). Herein, we present an overview of the current pharmacopeia of cellular senescence affecting compounds and evidence for their effects, if known, in murine and cellular models of MS. Consideration is also given to the utility of these compounds for the treatment of progressive MS, with an examination of past and current clinical trials that have tested these agents, often for other purposes, in the MS patient population.

Distinct profiles of cellular senescence-associated gene expression in the aged, diseased or injured central nervous system.

The molecular process of cellular senescence, which is known to contribute to aging, has been implicated in several diseases of the central nervous system (CNS). The purpose of this study was to generate an unbiased survey of cellular senescence gene expression with whole brain tissues using a standardized, curated set of 88 genes associated with cellular senescence. We performed a comparative analysis of aged brains with two CNS disease models; the 5xFAD mouse model of Alzheimer's disease, and cuprizone-induced CNS demyelination.

Astrocyte-Derived Extracellular Vesicles (ADEVs): Deciphering their Influences in Aging.

Astrocytes are an abundant and dynamic glial cell exclusive to the central nervous system (CNS). In the context of injury, inflammation, and/or diseases of the nervous system, astrocyte responses, termed reactive astrogliosis, are a recognized pathological feature across a range of conditions and diseases. However, the impact of reactive astrogliosis is not uniform and varies by context and duration (time).

Extracellular matrix influences astrocytic extracellular vesicle function in wound repair.

Astrocytic injury responses are known to be influenced by the extracellular matrix (ECM). Astrocytes are also recognized as a source of extracellular vesicles (EVs) that can impact the activity and function of other astrocytes and cell types. Whether the ECM influences the function of astrocytic EVs in the context of wound recovery has not been previously studied.

Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease.

Neonatal AAV9-gene therapy of the lysosomal enzyme galactosylceramidase (GALC) significantly ameliorates central and peripheral neuropathology, prolongs survival, and largely normalizes motor deficits in Twitcher mice. Despite these therapeutic milestones, new observations identified the presence of multiple small focal demyelinating areas in the brain after 6-8 months. These lesions are in stark contrast to the diffuse, global demyelination that affects the brain of naive Twitcher mice.

Mesenchyme-specific loss of Dot1L histone methyltransferase leads to skeletal dysplasia phenotype in mice.

Chromatin modifying enzymes play essential roles in skeletal development and bone maintenance, and deregulation of epigenetic mechanisms can lead to skeletal growth and malformation disorders. Here, we report a novel skeletal dysplasia phenotype in mice with conditional loss of Disruptor of telomeric silencing 1-like (Dot1L) histone methyltransferase in limb mesenchymal progenitors and downstream descendants. Phenotypic characterizations of mice with Dot1L inactivation by Prrx1-Cre (Dot1L-cKO) revealed limb shortening, abnormal bone morphologies, and forelimb dislocations.

Stem Cells of the Aging Brain.

The adult central nervous system (CNS) contains resident stem cells within specific niches that maintain a self-renewal and proliferative capacity to generate new neurons, astrocytes, and oligodendrocytes throughout adulthood. Physiological aging is associated with a progressive loss of function and a decline in the self-renewal and regenerative capacities of CNS stem cells. Also, the biggest risk factor for neurodegenerative diseases is age, and current and models of neurodegenerative diseases rarely consider this.

Astrocyte Support for Oligodendrocyte Differentiation can be Conveyed via Extracellular Vesicles but Diminishes with Age.

The aging brain is associated with significant changes in physiology that alter the tissue microenvironment of the central nervous system (CNS). In the aged CNS, increased demyelination has been associated with astrocyte hypertrophy and aging has been implicated as a basis for these pathological changes. Aging tissues accumulate chronic cellular stress, which can lead to the development of a pro-inflammatory phenotype that can be associated with cellular senescence.

The Effects of IL-1β on Astrocytes are Conveyed by Extracellular Vesicles and Influenced by Age.

The aging brain is associated with significant pathophysiological changes reflected in changes in astrocyte function. In this study, we hypothesized that the response of astrocytes to mechanical and inflammatory stimulation would differ with long-term culture. We report that naïve short-term cultured (young) and long-term cultured astrocytes (aged) exhibit similar recovery to a scratch wound assay.

Targeted Complement Inhibition at Synapses Prevents Microglial Synaptic Engulfment and Synapse Loss in Demyelinating Disease.

Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. While work has focused on myelin and axon loss in MS, less is known about mechanisms underlying synaptic changes. Using postmortem human MS tissue, a preclinical nonhuman primate model of MS, and two rodent models of demyelinating disease, we investigated synapse changes in the visual system.

TIMP-1 Attenuates the Development of Inflammatory Pain Through MMP-Dependent and Receptor-Mediated Cell Signaling Mechanisms.

Unresolved inflammation is a significant predictor for developing chronic pain, and targeting the mechanisms underlying inflammation offers opportunities for therapeutic intervention. During inflammation, matrix metalloproteinase (MMP) activity contributes to tissue remodeling and inflammatory signaling, and is regulated by tissue inhibitors of metalloproteinases (TIMPs). TIMP-1 and -2 have known roles in pain, but only in the context of MMP inhibition.

Systemic TLR2 tolerance enhances central nervous system remyelination.

Background: Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by both inflammatory demyelination and impaired remyelination. Studies indicate that Toll-like receptor 2 (TLR2) signaling contributes to both the inflammatory component and the defective remyelination in MS. While most MS therapeutics target adaptive immunity, we recently reported that reducing TLR2 signaling in innate immune cells by inducing TLR2 tolerance attenuates adoptively transferred experimental autoimmune encephalomyelitis.