Microglia-Astrocyte Crosstalk: An Intimate Molecular Conversation

Translating Stem Cell Studies to the Clinic for CNS Repair: Current State of the Art and the Need for a Rosetta Stone

Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases

Central nervous system (CNS) injuries, such as cerebral ischemia, traumatic brain injury (TBI), and spinal cord injury (SCI), are often accompanied by complex pathological changes, and could lead to a variety of other neurological diseases. Neurons and glial cells are precisely regulated by many genes. MicroRNA (miRNA) are endogenous molecules discovered in recent years that regulate post transcriptional gene expression. They are highly expressed in the central nervous system and abnormal expressed under pathological conditions. They are involved in regulating variety of pathological processes after CNS injuries, and are CNS disease potential biomarkers. (Chin J Lab Med, 2015, 38: 211–214) Key words: microRNAs; Brain ischemia; Brain injuries; Spinal cord injuries; Biological markers

BACKGROUND AND AIMS Neural cell adhesion molecule-1 (NCAM-1) has been found to be associated with central nervous system (CNS) injury in patients with lupus nephritis in small case series. This study aimed to explore the relationship between glomerular NCAM-1 expression and CNS injury in patients with membranous lupus nephritis (MLN) and the influence of NCAM-1 expression on the prognosis of MLN. METHOD 238 patients(47 class V, 132 mixed class V + III/IV, 46 class III/IV, 7 class II, 6 lupus podocytopathy) with SLE-associated CNS injury were screened from the LN cohort between 2009 and 2019. CNS injury was assessed by clinical and brain MRI. Patients without CNS injury were served as the control. The degree of electron-dense subepithelial deposits and proportion of podocyte foot process effacement (FPE) was assessed semi-quantitatively by electron microscopy. Kidney NCAM-1 was stained by immunohistochemistry. The NCAM-1 expression in patients with different classes of LN and its relationship with CNS injury was analyzed. RESULTS In total, positive NCAM-1 staining was found in 59 of 238 (24.8%) LN patients with CNS injury. NCAM-1 positive rates were significant higher in the cases with class V (22/47, 46.8%) and mixed class (35/132, 26.5%) than those with proliferative class (2/46, 4.3%), class II (0/7) and lupus podocytopathy (0/6). NCAM-1 positive rate was significantly higher in class V (46.8% versus 13.3%, P < 0.001) and mixed class (26.5% versus 7.3%, P < 0.001) patients with CNS injury than those patients without CNS injury. Compared with NCAM-1 negative MLN (included class V and mixed class) patients with CNS injury, NCAM-1 positive MLN patients had much higher proportion of nephrotic syndrome (54.4% versus 37.2%, P = 0.03), hypoalbuminemia (66.7% versus 49.2%, P = 0.029), extensive subepithelial immune deposits (56% versus 25.5%, P = 0.009) and proportion of FPE (75.4 ± 10.2% versus 68.1 ± 16.6%, P = 0.038), and significantly lower duration of SLE (12.0 (3.0, 48.0) months versus 26.0 (4.5, 84.0) months, P = 0.046) and renal CI score (2.0 (1.0, 3.0) versus 3.0 (2.0, 4.0), P < 0.001). No significant differences were found between the NCAM-1 positive and NCAM-1 negative MLN patients in the baseline SCr level, imaging features of brain MRI, extrarenal organ involvement and long-term patient and renal outcomes. CONCLUSION NCAM-1 is associated with MLN (including class V and mixed class) and CNS injury, and NCAM-1 positive MLN shows special clinicopathological features of renal injury, indicating that NCAM-1 positive MLN could be a subtype of MLN.

I N THIS issueof theARCHIVES, SchwabandSchlueseneraddress the roles of cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) in central nervous system (CNS) diseases and injury. First, they argue that COX-1 activity in CNS diseases has been overlooked. They point out that COX-1, although it is a constitutively expressed enzyme, accumulates under pathophysiologic conditions of chronic injury. Specifically, COX-1 is expressed in the microglia and macrophages that accumulate during recovery from hypoxicischemic or traumatic brain injury. It is also expressed in microglia and macrophages in Alzheimer disease. Second, Schwab and Schluesener also point out that our understanding of inflammation has recently been complicated by evidence suggesting that an initial proinflammatory burst of prostaglandin production can be followed by prostaglandin-mediated anti-inflammatory (reparative) responses. Evidence that COX-2 can play a role in the resolution of inflammation and wound healing in nonCNS tissues raises the possibility that COX-2 may have an as yet uncharacterized delayed reparative effect in CNS injury. Thus, Schwab and Schluesener argue that the emphasis on COX-2 as a pathogenic factor in CNS injury is misplaced. The hypothesis that COX-1 plays an important role in glial inflammation is well supported; both cyclooxygenase isoforms are expressed in activated glia. However, COX-2 is the predominant isoform within the neuron itself, has a special role in regulating synaptic activity, and contributes, at least in part, to neuronal death in a variety of disease states. Thus, we believe that the emphasis on COX-2 and the potential therapeutic use of selective COX-2 inhibitors in neurological diseases is well founded. Although the chemical properties of COX-2 and COX-1 are almost identical, COX-2 is expressed in different cellular and intracellular locations, and its expression is controlled by stimuli different than those for COX-1. The first-order product of both cyclooxygenase enzymes is prostaglandin H2, which is subsequently metabolized into prostaglandin D2, prostaglandin E2, prostaglandin F2 , prostacyclin, or thromboxane A2, depending on which specific prostaglandin synthases are expressed in that cell. Each of these first-order prostaglandins has specific receptors coupled to different second-messenger systems and biological responses. Thus, although COX-1 and COX-2 produce identical products, they are coupled to different physiologic responses utilizing different secondmessenger systems. The neuron is one cell type in whichCOX-2 ishighlyexpressed, and COX-2 may play a special role in normal neuronal function and in neuronal cell death. A special role of COX-2 within neurons was first elucidated by the studies of Yamagata et al, who cloned COX-2 from a rat seizure model. They found that COX-2 transcription is coupled to synaptic activity. Furthermore, N-methyl-Daspartate antagonists, such as MK801, block transcription of COX-2 induced by neuronal excitation, suggesting that COX-2 transcription is linked to increases in intracellular calcium. Consistent with this purported role in excitotoxic injury, COX-2 is expressed in the postsynaptic neuronal cell bodies of glutamatergic synapses. Interestingly, basal expression of COX-2 occurs primarily in the hippocampus and the limbic cortex, areas that are particularly vulnerable in hypoxicischemic injury and Alzheimer disease. COX-2 is also expressed in activated macrophages and in endothelial cells. Because inflammation isan importantphysiologiceffect ofcyclooxygenaseactivity, it is anatural assumption that activated macrophages and other inflammatory cells could mediate the pathologic effects of cyclooxygenase activity. In contrast, endothelial cell COX-2– dependent production of the potent vasodilator prostacyclin can increase blood flow and attenuate acute ischemic injury. Recent studies conclusively demonstrate that cyclooxygenase activity within the neuron itself can directly injure neurons independent of any effects on glial cells or blood flow. Hewett et al found that N-methylD-aspartate–induced cell injury could be ameliorated by treatment with selective COX-2 inhibitors. Li and Graham found that COX-2 inhibitors, From the Geriatric Research Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System (Dr Graham), and the Departments of Neurology (Dr Graham) and Pediatrics (Dr Hickey), University of Pittsburgh School of Medicine, Pittsburgh, Pa. SECTION EDITOR: STEVEN T. DEKOSKY, MD CONTROVERSIES IN NEUROLOGY

As an iron-dependent regulated form of cell death, ferroptosis is characterized by iron-dependent lipid peroxidation and has been implicated in the occurrence and development of various diseases, including nervous system diseases and injuries. Ferroptosis has become a potential target for intervention in these diseases or injuries in relevant preclinical models. As a member of the Acyl-CoA synthetase long-chain family (ACSLs) that can convert saturated and unsaturated fatty acids, Acyl-CoA synthetase long-chain familymember4 (ACSL4) is involved in the regulation of arachidonic acid and eicosapentaenoic acid, thus leading to ferroptosis. The underlying molecular mechanisms of ACSL4-mediated ferroptosis will promote additional treatment strategies for these diseases or injury conditions. Our review article provides a current view of ACSL4-mediated ferroptosis, mainly including the structure and function of ACSL4, as well as the role of ACSL4 in ferroptosis. We also summarize the latest research progress of ACSL4-mediated ferroptosis in central nervous system injuries and diseases, further proving that ACSL4-medicated ferroptosis is an important target for intervention in these diseases or injuries.

Microglia, the resident immune cells of the central nervous system (CNS), play an important role in CNS homeostasis during development, adulthood and ageing. Their phenotype and function have been widely studied, but most studies have focused on their local interactions in the CNS. Microglia are derived from a particular developmental niche, are long-lived, locally replaced and form a significant part of the communication route between the peripheral immune system and the CNS; all these components of microglia biology contribute to maintaining homeostasis. Microglia function is tightly regulated by the CNS microenvironment, and increasing evidence suggests that disturbances, such as neurodegeneration and ageing, can have profound consequences for microglial phenotype and function. We describe the possible biological mechanisms underlying the altered threshold for microglial activation, also known as ‘microglial priming’, seen in CNS disease and ageing and consider how priming may contribute to turning immune-to-brain communication from a homeostatic pathway into a maladaptive response that contributes to symptoms and progression of diseases of the CNS.

Arginase-1 is expressed exclusively by infiltrating myeloid cells in CNS injury and disease

The health of the central nervous system (CNS) is a subject that impacts on all people and especially on those who have the misfortune to be afflicted by CNS injury or disease. The cerebrovascular barriers at the CNS capillaries and the choroid plexus play a vital role in maintaining the microenvironment of the cells in the brain and spinal cord. The stated aim of this book is to act as a stimulus for research directed towards minimizing the effects of CNS stress, injuries and insults. With seven sections that include 27 chapters from 59 contributors and 605 pages in total, this book covers many topics including: basic aspects of the barriers, in vitro models, physiological transport mechanisms, neurochemical mediators, stress situations, changes in disease conditions and clinical aspects. Each chapter consists of a review, together with up-to-date original data. The chapters are laid out clearly in a consistent format with informative illustrations. This is an important wide-ranging book aimed at researchers in neuroscience, drug discovery and development, and neuropathology. Although large, it contains a wealth of information on contemporary research with an impressive 29-page index from arachadonic acid to zonula occludens proteins. The bulk of the text deals with research relating to the cerebrovascular barriers in the brain. However, in contrast with past books on the blood-brain barriers, this one contains several chapters concerned with the blood-spinal cord barrier. Considering the volume of research on spinal cord injury in recent decades, this serves as a useful source of information and a reminder that barrier function is important throughout the CNS. Furthermore, it reinforces the probability that information obtained from research on barriers in the brain can be applied to the therapeutic treatment of spinal cord injury. One rather disappointing aspect of this otherwise excellent book is the small amount of space devoted to the choroid plexus and the cerebrospinal fluid (CSF). This is the alternative route to the brain, the blood-CSF barrier with somewhat different properties to the blood-brain barrier. Only two chapters contribute to this very important aspect of brain homeostasis and to the potential for manipulation of the CSF for diagnostic and therapeutic purposes. Overall, 'Blood-Spinal Cord and Brain Barriers in Health and Disease' is a contemporary and very informative volume that should be a ready source of reference for all researchers and clinicians concerned with the CNS in health and disease.

To describe a salt-wasting syndrome in children with central nervous system (CNS) insults and to differentiate it from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and diabetes insipidus so that it may be more readily diagnosed and treated. Case reports. Community teaching hospital. Two inpatients with CNS insults (closed head trauma in one and seizure disorder, spastic diplegia, mental retardation, and hydrocephalus in the other). Evidence of hyponatremia accompanied by elevated urine sodium concentration and excessive urine output. Volume-for-volume urine replacement with 0.9% and/or 3% sodium chloride. Oral salt supplementation was required for brief periods to maintain normal plasma sodium concentration after discharge from the hospital. Both patients had hyponatremia, high urine sodium concentrations, hypovolemia, and excessive urine output while receiving maintenance fluids. They also had elevated plasma atrial natriuretic hormone (ANH) concentrations, decreased aldosterone concentrations, and decreased [corrected] plasma renin activity for their degree of hyponatremia and negative fluid balance. Both patients maintained normal serum electrolyte concentrations with appropriate treatment. These patients showed true salt wasting associated with acute or chronic CNS injury, with hormonal patterns consistent with "inappropriate" ANH secretion and distinct from the SIADH. It is important to distinguish cerebral salt wasting (CSW) from the two other major disturbances of water metabolism seen following CNS injury (ie, SIADH and diabetes insipidus), because incorrect diagnosis and treatment could greatly increase morbidity in CSW. The etiologic roles of ANH or brain natriuretic peptide in CSW need to be further elucidated.

The blood-brain barrier (BBB) is a term used to describe a series of properties possessed by the vasculature of the central nervous system (CNS) that tightly regulate the movement of ions, molecules, and cells between the blood and the CNS. This barrier is crucial to provide the appropriate environment to allow for proper neural function, as well as protect the CNS from injury and disease. In this review, I discuss the cellular and molecular composition of the BBB and how the development and function of the BBB is regulated by interactions with the CNS microenvironment. I further discuss what is known about BBB dysfunction during CNS injury and disease, as well as methodology used to deliver drugs across the BBB to the CNS.

The Central Nervous System Microenvironment Influences the Leukemia Transcriptome and Enhances Leukemia Chemo-Resistance

The CNS Microenvironment Promotes Leukemia Cell Survival By Disrupting Tumour Suppression and Cell Cycle Regulation in Pediatric T-Cell Acute Lymphoblastic Leukemia

Objective To investigate the expression of central nervous system specific protein (S100) in cerebrospinal fluid, glial fibrillary acidic protein (GFAP), neuronspecific enolase (NSE) and myelin basic protein (MBP) in the central nervous system. Methods The clinical data of 82 children with convulsions in Qilu Hospital of Shandong University from February 2017 to May 2018 were analyzed retrospectively. According to the causes of seizure, the 25 cases of febrile convulsion were selected as febrile convulsion group, 28 cases of viral meningitis were selected as viral meningitis group, and 29 patients with epilepsy were selected into epilepsy group. During the same period, 36 children with suspected central nervous system diseases who were eventually diagnosed as healthy were enrolled in the health group. The contents of S100β, GFAP, NSE and MBP in cerebrospinal fluid of each group were determined by enzyme-linked immunosorbent assay (ELISA), and their correlation with different kinds of convulsions was analyzed. Results The levels of S100β, GFAP, NSE and MBP in cerebrospinal fluid in health group were lower than those in febrile convulsion group, viral encephalitis group and epilepsy group, the differences were significant (P 0.05). Conclusions Protein markers such as S100β, GFAP, NSE and MBP in cerebrospinal fluid are highly expressed in children with central nervous system injury. They can be monitored clinically, and assess the child’s condition. Key words: Central nervous system injury; Cerebrospinal fluid; Protein; Correlation

Some studies report neurological lesions in patients with genetic skeletal disorders (GSDs). However, none of them describe the frequency of neurological lesions in a large sample of patients or investigate the associations between clinical and/or radiological central nervous system (CNS) injury and clinical, anthropometric and imaging parameters. The project was approved by the institution’s ethics committee (CAAE 49433215.5.0000.0022). In this cross-sectional observational analysis study, 272 patients aged four or more years with clinically and radiologically confirmed GSDs were prospectively included. Genetic testing confirmed the diagnosis in the FGFR3 chondrodysplasias group. All patients underwent blinded and independent clinical, anthropometric and neuroaxis imaging evaluations. Information on the presence of headache, neuropsychomotor development (NPMD), low back pain, joint deformity, ligament laxity and lower limb discrepancy was collected. Imaging abnormalities of the axial skeleton and CNS were investigated by whole spine digital radiography, craniocervical junction CT and brain and spine MRI. The diagnostic criteria for CNS injury were abnormal clinical and/or radiographic examination of the CNS. Brain injury included malacia, encephalopathies and malformation. Spinal cord injury included malacia, hydrosyringomyelia and spinal cord injury without radiographic abnormalities. CNS injury was diagnosed in more than 25% of GSD patients. Spinal cord injury was found in 21.7% of patients, and brain injury was found in 5.9%. The presence of low back pain, os odontoideum and abnormal NPMD remained independently associated with CNS injury in the multivariable analysis. Early identification of these abnormalities may have some role in preventing compressive CNS injury, which is a priority in GSD patients.