scholarly journals An atypical role for the myeloid receptor Mincle in CNS injury

2016 ◽  
Author(s):  
Thiruma V. Arumugam ◽  
Silvia Manzanero ◽  
Milena Furtado ◽  
Patrick J. Biggins ◽  
Yu-Hsuan Hsieh ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cerebral Ischemia ◽  
Functional Outcome ◽  
Research Council ◽  
Tissue Injury ◽  
Focal Cerebral Ischemia ◽  
Sterile Inflammation ◽  
Peripheral Tissues ◽  
The Brain

AbstractMincle is a C-type lectin known to play a role in innate immune responses to sterile inflammation, but its contribution to pathologies following an ischemic or traumatic injury is not well understood. In the current study we demonstrate a key role for Mincle in ischemic (i.e. transient middle cerebral artery occlusion) but not traumatic central nervous system injury; absence of Mincle also did not significantly alter the extent of tissue damage or functional outcome in peripheral models of ischemic tissue injury. In the stroke model mice lacking Mincle displayed significantly improved functional outcome from focal cerebral ischemia. The functional improvements in Mincle KO animals were accompanied by reduced infiltration of neutrophils and lower levels of proinflammatory cytokines in recruited peripheral blood cells. Bone marrow chimera experiments revealed that presence of Mincle in the central nervous system, but not peripheral immune cells, was the critical regulator of a poor outcome following transient focal cerebral ischemia, however we exclude a direct role for Mincle in microglia or neural activation. We demonstrate that Mincle lacks widespread expression in the brain, but is specifically associated with macrophages resident in the perivascular niche. These findings implicate Mincle in the initiation, extent and severity of local responses to ischemic injury in the brain, but not peripheral tissues. Mincle signalling therefore offers a novel therapeutic target in the quest to limit damage after stroke.Sources of support:Australian National Health & Medical Research Council [1057846, 1060538 and Fellowship to NAR], SpinalCure Australia (Career Development Fellowship to MJR), the Australian Research Council, the State Government of Victoria, the Australian Government and The University of Queensland.

CCL2 (C-C Motif Chemokine Ligand 2) Biomarker Responses in Central Versus Peripheral Compartments After Focal Cerebral Ischemia

Stroke ◽  
2021 ◽  
Author(s):  
Jingfei Shi ◽  
Wenlu Li ◽  
Fang Zhang ◽  
Ji Hyun Park ◽  
Hong An ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cerebral Ischemia ◽  
Nonhuman Primate ◽  
Direct Relationship ◽  
Focal Cerebral Ischemia ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Chemokine Ligand ◽  
Chemokine Ligand 2

Background and Purpose: Inflammatory mediators in blood have been proposed as potential biomarkers in stroke. However, a direct relationship between these circulating factors and brain-specific ischemic injury remains to be fully defined. Methods: An unbiased screen in a nonhuman primate model of stroke was used to find out the most responsive circulating biomarker flowing ischemic stroke. Then this phenomenon was checked in human beings and mice. Finally, we observed the temporospatial responsive characteristics of this biomarker after ischemic brain injury in mice to evaluate the direct relationship between this circulating factor and central nervous system–specific ischemic injury. Results: In a nonhuman primate model, an unbiased screen revealed CCL2 (C-C motif chemokine ligand 2) as a major response factor in plasma after stroke. In mouse models of focal cerebral ischemia, plasma levels of CCL2 showed a transient response, that is, rapidly elevated by 2 to 3 hours postischemia but then renormalized back to baseline levels by 24 hours. However, a different CCL2 temporal profile was observed in whole brain homogenate, cerebrospinal fluid, and isolated brain microvessels, with a progressive increase over 24 hours, demonstrating a mismatch between brain versus plasma responses. In contrast to the lack of correlation with central nervous system responses, 2 peripheral compartments showed transient profiles that matched circulating plasma signatures. CCL2 protein in lymph nodes and adipose tissue was significantly increased at 2 hours and renormalized by 24 hours. Conclusions: These findings may provide a cautionary tale for biomarker pursuits in plasma. Besides a direct central nervous system response, peripheral organs may also contribute to blood signatures in complex and indirect ways.

scholarly journals Immunology and Oxidative Stress in Multiple Sclerosis: Clinical and Basic Approach

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Genaro G. Ortiz ◽  
Fermín P. Pacheco-Moisés ◽  
Oscar K. Bitzer-Quintero ◽  
Ana C. Ramírez-Anguiano ◽  
Luis J. Flores-Alvarado ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Tissue Injury ◽  
Autoimmune Disorder ◽  
Demyelinating Lesions ◽  
The Central Nervous System ◽  
The Brain ◽  
And Oxidative Stress

Multiple sclerosis (MS) exhibits many of the hallmarks of an inflammatory autoimmune disorder including breakdown of the blood-brain barrier (BBB), the recruitment of lymphocytes, microglia, and macrophages to lesion sites, the presence of multiple lesions, generally being more pronounced in the brain stem and spinal cord, the predominantly perivascular location of lesions, the temporal maturation of lesions from inflammation through demyelination, to gliosis and partial remyelination, and the presence of immunoglobulin in the central nervous system and cerebrospinal fluid. Lymphocytes activated in the periphery infiltrate the central nervous system to trigger a local immune response that ultimately damages myelin and axons. Pro-inflammatory cytokines amplify the inflammatory cascade by compromising the BBB, recruiting immune cells from the periphery, and activating resident microglia. inflammation-associated oxidative burst in activated microglia and macrophages plays an important role in the demyelination and free radical-mediated tissue injury in the pathogenesis of MS. The inflammatory environment in demyelinating lesions leads to the generation of oxygen- and nitrogen-free radicals as well as proinflammatory cytokines which contribute to the development and progression of the disease. Inflammation can lead to oxidative stress and vice versa. Thus, oxidative stress and inflammation are involved in a self-perpetuating cycle.

scholarly journals Cerebral Apolipoprotein D Exits the Brain and Accumulates in Peripheral Tissues

2021 ◽  
Vol 22 (8) ◽  
pp. 4118
Author(s):  
Frederik Desmarais ◽  
Vincent Hervé ◽  
Karl F. Bergeron ◽  
Gaétan Ravaut ◽  
Morgane Perrotte ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cell Types ◽  
Strongly Correlated ◽  
Peripheral Tissues ◽  
Additional Cell ◽  
The Central Nervous System ◽  
Apolipoprotein D ◽  
Pass Through ◽  
The Brain

Apolipoprotein D (ApoD) is a secreted lipocalin associated with neuroprotection and lipid metabolism. In rodent, the bulk of its expression occurs in the central nervous system. Despite this, ApoD has profound effects in peripheral tissues, indicating that neural ApoD may reach peripheral organs. We endeavor to determine if cerebral ApoD can reach the circulation and accumulate in peripheral tissues. Three hours was necessary for over 40% of all the radiolabeled human ApoD (hApoD), injected bilaterally, to exit the central nervous system (CNS). Once in circulation, hApoD accumulates mostly in the kidneys/urine, liver, and muscles. Accumulation specificity of hApoD in these tissues was strongly correlated with the expression of lowly glycosylated basigin (BSG, CD147). hApoD was observed to pass through bEnd.3 blood brain barrier endothelial cells monolayers. However, cyclophilin A did not impact hApoD internalization rates in bEnd.3, indicating that ApoD exit from the brain is either independent of BSG or relies on additional cell types. Overall, our data showed that ApoD can quickly and efficiently exit the CNS and reach the liver and kidneys/urine, organs linked to the recycling and excretion of lipids and toxins. This indicated that cerebral overexpression during neurodegenerative episodes may serve to evacuate neurotoxic ApoD ligands from the CNS.

scholarly journals Type 3 Deiodinase Deficiency Causes Spatial and Temporal Alterations in Brain T3 Signaling that Are Dissociated from Serum Thyroid Hormone Levels

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5550-5558 ◽  
Author(s):  
Arturo Hernandez ◽  
Laure Quignodon ◽  
M. Elena Martinez ◽  
Frederic Flamant ◽  
Donald L. St. Germain
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Elevated Serum ◽  
Adult Brain ◽  
Neural Function ◽  
Peripheral Tissues ◽  
Show Evidence ◽  
The Central Nervous System ◽  
Type 3 ◽  
The Brain

The type 3 deiodinase (D3) is an enzyme that inactivates thyroid hormones (TH) and is highly expressed during development and in the central nervous system. D3-deficient (D3KO) mice develop markedly elevated serum T3 level in the perinatal period. In adulthood, circulating T4 and T3 levels are reduced due to functional deficits in the thyroid axis and peripheral tissues (i.e. liver) show evidence of decreased TH action. Given the importance of TH for brain development, we aimed to assess TH action in the brain of D3KO mice at different developmental stages and determine to what extent it correlates with serum TH parameters. We used a transgenic mouse model (FINDT3) that expresses the reporter gene β-galactosidase (β-gal) in the central nervous system as a readout of local TH availability. Together with experiments determining expression levels of TH-regulated genes, our results show that after a state of thyrotoxicosis in early development, most regions of the D3KO brain show evidence of decreased TH action at weaning age. However, later in adulthood and in old age, the brain again manifests a thyrotoxic state, despite reduced serum TH levels. These region-specific changes in brain TH status during the life span of the animal provide novel insight into the important role of the D3 in the developing and adult brain. Our results suggest that, even if serum concentrations of TH are normal or low, impaired D3 activity may result in excessive TH action in multiple brain regions, with potential consequences of altered neural function that may be of clinical relevance to neurological and neuroendocrine disorders.

Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system

2004 ◽  
Vol 91 (03) ◽  
pp. 457-464 ◽  
Author(s):  
Manuel Yepes ◽  
Daniel Lawrence
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Synaptic Plasticity ◽  
Cerebral Ischemia ◽  
Inclusion Bodies ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
The Central Nervous System ◽  
The Brain

SummaryNeuroserpin is a member of the serine proteinase inhibitor (serpin) gene family that reacts preferentially with tissue-type plasminogen activator (tPA) and is primarily localized to neurons in regions of the brain where tPA is also found. Outside of the central nervous system (CNS) tPA is predominantly found in the blood where its primary function is as a thrombolytic enzyme. However, tPA is also expressed within the CNS where it has a very different function, promoting events associated not only with synaptic plasticity but also with cell death in a number of settings, such as cerebral ischemia and seizures. Neuroserpin is released from neurons in response to neuronal depolarization and plays an important role in the development of synaptic plasticity. Following the onset of cerebral ischemia there is an increase in both tPA activity and neuroserpin expression in the area surrounding the necrotic core (ischemic penumbra), and treatment with neuroserpin following ischemic stroke or overexpression of the neuroserpin gene results in a significant decrease in the volume of the ischemic area as well as in the number of apoptotic cells. TPA activity and neuroserpin expression are also increased in specific areas of the brain by seizures, and treatment with neuroserpin slows the progression of seizure activity throughout the CNS and results in significant neuronal survival in the hippocampus. Mutations in human neuroserpin result in a form of autosomal dominant inherited dementia which is characterized by the presence of intraneuronal inclusion bodies and is known as Familial Encephalopathy with Neuroserpin Inclusion Bodies.

Primary central nervous system lymphoma: tumor-related clones exist in the blood and bone marrow with evidence for separate development

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4677-4680 ◽  
Author(s):  
Katy J. McCann ◽  
Margaret Ashton-Key ◽  
KellyAnn Smith ◽  
Freda K. Stevenson ◽  
Christian H. Ottensmeier
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Tumor Cells ◽  
Environmental Influence ◽  
Systemic Disease ◽  
Cns Lymphoma ◽  
Peripheral Tissues ◽  
V Gene ◽  
The Brain

Abstract Primary central nervous system (CNS) lymphoma is an aggressive B-cell tumor that is defined clinically by the absence of systemic disease. We have used immunoglobulin variable (V)–gene analysis to identify tumor cells at the CNS site in 12 cases and to probe the involvement of peripheral tissues in 3 patients. Clonal tracking revealed tumor cells in the bone marrow and/or blood for 3 of 3 cases, with evidence for increased V-gene mutational activity at peripheral sites. In 2 of 3 cases, intraclonal variant analysis revealed identity with the brain biopsy but detected additional variants unique to extracerebral sites. These findings suggest that peripheral tumor cells can undergo separate development locally with no reentry into the brain. Primary CNS lymphoma appears to have both CNS-specific and systemic components with limited interchange. The more malignant behavior of tumor cells in the CNS suggests either a local environmental influence or a less malignant phenotype of the peripheral clone.

STEREOTACTIC RADIOSURGERY: ADJACENT TISSUE INJURY AND RESPONSE AFTERHIGH-DOSE SINGLE FRACTION RADIATION

Neurosurgery ◽  
2007 ◽  
Vol 60 (1) ◽  
pp. 31-45 ◽  
Author(s):  
Bryan C. Oh ◽  
Paul G. Pagnini ◽  
Michael Y. Wang ◽  
Charles Y. Liu ◽  
Paul E. Kim ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Tissue Injury ◽  
Molecular Data ◽  
Benign Tumors ◽  
Normal Brain ◽  
Clinical Scenarios ◽  
The Central Nervous System ◽  
Brain Parenchymal ◽  
The Brain

Abstract RADIOSURGERY IS NOW the preferred treatment modality for many intracranial disease processes. Although almost 50 years have passed since it was introduced as a tool to treat neurological disease, investigations into its effects on normal tissues of the central nervous system are still ongoing. The need for these continuing studies must be underscored. A fundamental understanding of the brain parenchymal response to radiosurgery would permit development of strategies that would enhance and potentiate the radiosurgical treatment effects on diseased tissue while mitigating injury to normal structures. To date, most studies on the response of the central nervous system to radiosurgery have been performed on brain tissue in the absence of pathological lesions, such as benign tumors or metastases. Although instructive, these investigations fail to emulate the majority of clinical scenarios that involve radiosurgical treatment of specific lesions surrounded by normal brain parenchyma. This article is the first in a two-part series that addresses the brain parenchyma's response to radiosurgery. This first article analyzes the histological, radiographic, and molecular data gathered regarding the brain parenchymal response to radiosurgery and aims to suggest future studies that could enhance our understanding of the topic. The second article in the series begins by discussing strategies for radiosurgical therapeutic enhancement. It concludes by focusing on strategies for mitigation and repair of radiation-induced brain injury.

scholarly journals The Complex Interplay between Endocannabinoid System and the Estrogen System in Central Nervous System and Periphery

2021 ◽  
Vol 22 (2) ◽  
pp. 972 ◽  
Author(s):  
Antonietta Santoro ◽  
Elena Mele ◽  
Marianna Marino ◽  
Andrea Viggiano ◽  
Stefania Lucia Nori ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cell Signaling ◽  
Endocannabinoid System ◽  
Peripheral Tissues ◽  
Signaling Systems ◽  
Cell Responses ◽  
The Central Nervous System ◽  
The Brain ◽  
Neuroendocrine Functions

The endocannabinoid system (ECS) is a lipid cell signaling system involved in the physiology and homeostasis of the brain and peripheral tissues. Synaptic plasticity, neuroendocrine functions, reproduction, and immune response among others all require the activity of functional ECS, with the onset of disease in case of ECS impairment. Estrogens, classically considered as female steroid hormones, regulate growth, differentiation, and many other functions in a broad range of target tissues and both sexes through the activation of nuclear and membrane estrogen receptors (ERs), which leads to genomic and non-genomic cell responses. Since ECS function overlaps or integrates with many other cell signaling systems, this review aims at updating the knowledge about the possible crosstalk between ECS and estrogen system (ES) at both central and peripheral level, with focuses on the central nervous system, reproduction, and cancer.

Glucuronyl 3-sulfate occurs exclusively on distal unmyelinated terminals of selected sensory neurons in the peripheral nervous system

1995 ◽  
Vol 53 ◽  
pp. 958-959
Author(s):  
S.S. Spicer ◽  
B.A. Schulte
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cerebral Cortex ◽  
Peripheral Nervous System ◽  
Sensory Neurons ◽  
Sensory Nerves ◽  
Tissue Antigens ◽  
The Central Nervous System ◽  
The Brain ◽  
Leu 7

Generation of monoclonal antibodies (MAbs) against tissue antigens has yielded several (VC1.1, HNK- 1, L2, 4F4 and anti-leu 7) which recognize the unique sugar epitope, glucuronyl 3-sulfate (Glc A3- SO4). In the central nervous system, these MAbs have demonstrated Glc A3-SO4 at the surface of neurons in the cerebral cortex, the cerebellum, the retina and other widespread regions of the brain.Here we describe the distribution of Glc A3-SO4 in the peripheral nervous system as determined by immunostaining with a MAb (VC 1.1) developed against antigen in the cat visual cortex. Outside the central nervous system, immunoreactivity was observed only in peripheral terminals of selected sensory nerves conducting transduction signals for touch, hearing, balance and taste. On the glassy membrane of the sinus hair in murine nasal skin, just deep to the ringwurt, VC 1.1 delineated an intensely stained, plaque-like area (Fig. 1). This previously unrecognized structure of the nasal vibrissae presumably serves as a tactile end organ and to our knowledge is not demonstrable by means other than its selective immunopositivity with VC1.1 and its appearance as a densely fibrillar area in H&E stained sections.

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