The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms ...underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E
(PGE
), which stimulates β-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE
production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.
Lipocalin‐2 (LCN2) has diverse functions in multiple pathophysiological conditions; however, its pathogenic role in vascular dementia (VaD) is unknown. Here, we investigated the role of LCN2 in VaD ...using rodent models of global cerebral ischemia and hypoperfusion with cognitive impairment and neuroinflammation. Mice subjected to transient bilateral common carotid artery occlusion (tBCCAo) for 50 min showed neuronal death and gliosis in the hippocampus at 7 days post‐tBCCAo. LCN2 expression was observed predominantly in the hippocampal astrocytes, whereas its receptor was mainly detected in neurons, microglia, and astrocytes. Furthermore, Lcn2‐deficient mice, compared with wild‐type animals, showed significantly weaker CA1 neuronal loss, cognitive decline, white matter damage, blood–brain barrier permeability, glial activation, and proinflammatory cytokine production in the hippocampus after tBCCAo. Lcn2 deficiency also attenuated hippocampal neuronal death and cognitive decline at 30 days after unilateral common carotid artery occlusion (UCCAo). Furthermore, intracerebroventricular (i.c.v) injection of recombinant LCN2 protein elicited CA1‐neuronal death and a cognitive deficit. Our studies using cultured glia and hippocampal neurons supported the decisive role of LCN2 in hippocampal neurotoxicity and microglial activation, and the role of the HIF‐1α–LCN2–VEGFA axis of astrocytes in vascular injury. Additionally, plasma levels of LCN2 were significantly higher in patients with VaD than in the healthy control subjects. These results indicate that hippocampal damage and cognitive impairment are mediated by LCN2 secreted from reactive astrocytes in VaD.
Main Points
Astrocyte‐derived LCN2 mediates hippocampal damage in rodent models of vascular dementia, with higher plasma levels of LCN2 protein in patients with vascular dementia, suggesting the possibility of effective glia‐based treatment for vascular dementia.
Orosomucoid (ORM) is an acute-phase protein that belongs to the immunocalin subfamily, a group of small-molecule-binding proteins with immunomodulatory functions. Little is known about the role of ...ORM proteins in the CNS. The aim of the present study was to investigate the brain expression of ORM and its role in neuroinflammation. Expression of Orm2, but not Orm1 or Orm3, was highly induced in the mouse brain after systemic injection of lipopolysaccharide (LPS). Plasma levels of ORM2 were also significantly higher in patients with cognitive impairment than in normal subjects. RT-PCR, Western blot, and immunofluorescence analyses revealed that astrocytes are the major cellular sources of ORM2 in the inflamed mouse brain. Recombinant ORM2 protein treatment decreased microglial production of proinflammatory mediators and reduced microglia-mediated neurotoxicity
LPS-induced microglial activation, proinflammatory cytokines in hippocampus, and neuroinflammation-associated cognitive deficits also decreased as a result of intracerebroventricular injection of recombinant ORM2 protein
Moreover, lentiviral shRNA-mediated Orm2 knockdown enhanced LPS-induced proinflammatory cytokine gene expression and microglial activation in the hippocampus. Mechanistically, ORM2 inhibited C-C chemokine ligand 4 (CCL4)-induced microglial migration and activation by blocking the interaction of CCL4 with C-C chemokine receptor type 5. Together, the results from our cultured glial cells, mouse neuroinflammation model, and patient studies suggest that ORM2 is a novel mediator of astrocyte-microglial interaction. We also report that ORM2 exerts anti-inflammatory effects by modulating microglial activation and migration during brain inflammation. ORM2 can be exploited therapeutically for the treatment of neuroinflammatory diseases.
Neural cell interactions are important for brain physiology and pathology. Particularly, the interaction between non-neuronal cells plays a central role in regulating brain inflammation, which is closely linked to many brain disorders. Here, we newly identified orosomucoid-2 (ORM2) as an endogenous protein that mediates such non-neuronal glial cell interactions. Based on the critical role of astrocyte-derived ORM2 in modulating microglia-mediated neuroinflammation, ORM2 can be exploited for the diagnosis, prevention, or treatment of devastating brain disorders that have a strong neuroinflammatory component, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis.
Activated macrophages are classified into two different forms: classically activated (M1) or alternatively activated (M2) macrophages. The presence of M1/M2 phenotypic polarization has also been ...suggested for microglia. Here, we report that the secreted protein lipocalin 2 (LCN2) amplifies M1 polarization of activated microglia. LCN2 protein (EC50 1 μg/ml), but not glutathione S‐transferase used as a control, increased the M1‐related gene expression in cultured mouse microglial cells after 8–24 h. LCN2 was secreted from M1‐polarized, but not M2‐polarized, microglia. LCN2 inhibited phosphorylation of STAT6 in IL‐4‐stimulated microglia, suggesting LCN2 suppression of the canonical M2 signaling. In the lipopolysaccharide (LPS)‐induced mouse neuroinflammation model, the expression of LCN2 was notably increased in microglia. Primary microglial cultures derived from LCN2‐deficient mice showed a suppressed M1 response and enhanced M2 response. Mice lacking LCN2 showed a markedly reduced M1‐related gene expression in microglia after LPS injection, which was consistent with the results of histological analysis. Neuroinflammation‐associated impairment in motor behavior and cognitive function was also attenuated in the LCN2‐deficient mice, as determined by the rotarod performance test, fatigue test, open‐field test, and object recognition task. These findings suggest that LCN2 is an M1‐amplifier in brain microglial cells.—Jang, E., Lee, S., Kim, J.‐H., Kim, J.‐H., Seo, J.‐W., Lee, W.‐H., Mori, K., Nakao, K., Suk, K. Secreted protein lipocalin‐2 promotes microglial M1 polarization. FASEB J. 27, 1176–1190 (2013). www.fasebj.org
Thin-film transistor (TFT)-driven full-color organic light-emitting diodes (OLEDs) with vertically stacked structures are developed herein using photolithography processes, which allow for ...high-resolution displays of over 2,000 pixels per inch. Vertical stacking of OLEDs by the photolithography process is technically challenging, as OLEDs are vulnerable to moisture, oxygen, solutions for photolithography processes, and temperatures over 100 °C. In this study, we develop a low-temperature processed Al
O
/SiN
bilayered protection layer, which stably protects the OLEDs from photolithography process solutions, as well as from moisture and oxygen. As a result, transparent intermediate electrodes are patterned on top of the OLED elements without degrading the OLED, thereby enabling to fabricate the vertically stacked OLED. The aperture ratio of the full-color-driven OLED pixel is approximately twice as large as conventional sub-pixel structures, due to geometric advantage, despite the TFT integration. To the best of our knowledge, we first demonstrate the TFT-driven vertically stacked full-color OLED.
Glial cells are multifunctional, non-neuronal components of the central nervous system with diverse phenotypes that have gained much attention for their close involvement in neuroinflammation and ...neurodegenerative diseases. Glial phenotypes are primarily characterized by their structural and functional changes in response to various stimuli, which can be either neuroprotective or neurotoxic. The reliance of neurons on glial cells is essential to fulfill the energy demands of the brain for its proper functioning. Moreover, the glial cells perform distinct functions to regulate their own metabolic activities, as well as work in close conjunction with neurons through various secreted signaling or guidance molecules, thereby constituting a complex network of neuron-glial interactions in health and disease. The emerging evidence suggests that, in disease conditions, the metabolic alterations in the glial cells can induce structural and functional changes together with neuronal dysfunction indicating the importance of neuron-glia interactions in the pathophysiology of neurological disorders. This review covers the recent developments that implicate the regulation of glial phenotypic changes and its consequences on neuron-glia interactions in neurological disorders. Finally, we discuss the possibilities and challenges of targeting glial metabolism as a strategy to treat neurological disorders.
Astrocytes, which are homeostatic cells of the central nervous system (CNS), display remarkable heterogeneity in their morphology and function. Besides their physical and metabolic support to ...neurons, astrocytes modulate the blood-brain barrier, regulate CNS synaptogenesis, guide axon pathfinding, maintain brain homeostasis, affect neuronal development and plasticity, and contribute to diverse neuropathologies via secreted proteins. The identification of astrocytic proteome and secretome profiles has provided new insights into the maintenance of neuronal health and survival, the pathogenesis of brain injury, and neurodegeneration. Recent advances in proteomics research have provided an excellent catalog of astrocyte-secreted proteins. This review categorizes astrocyte-secreted proteins and discusses evidence that astrocytes play a crucial role in neuronal activity and brain function. An in-depth understanding of astrocyte-secreted proteins and their pathways is pivotal for the development of novel strategies for restoring brain homeostasis, limiting brain injury/inflammation, counteracting neurodegeneration, and obtaining functional recovery.
Abstract
Single-phase multiferroic materials that allow the coexistence of ferroelectric and magnetic ordering above room temperature are highly desirable, motivating an ongoing search for mechanisms ...for unconventional ferroelectricity in magnetic oxides. Here, we report an antisite defect mechanism for room temperature ferroelectricity in epitaxial thin films of yttrium orthoferrite, YFeO
3
, a perovskite-structured canted antiferromagnet. A combination of piezoresponse force microscopy, atomically resolved elemental mapping with aberration corrected scanning transmission electron microscopy and density functional theory calculations reveals that the presence of Y
Fe
antisite defects facilitates a non-centrosymmetric distortion promoting ferroelectricity. This mechanism is predicted to work analogously for other rare earth orthoferrites, with a dependence of the polarization on the radius of the rare earth cation. Our work uncovers the distinctive role of antisite defects in providing a mechanism for ferroelectricity in a range of magnetic orthoferrites and further augments the functionality of this family of complex oxides for multiferroic applications.
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