scholarly journals Central Nervous System Barriers Impact Distribution and Expression of iNOS and Arginase-1 in Infiltrating Macrophages During Neuroinflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Daniela C. Ivan ◽  
Sabrina Walthert ◽  
Giuseppe Locatelli
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Differential Distribution ◽  
General Ability ◽  
Border Regions ◽  
Arginase 1 ◽  
Tnf Α ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory

In multiple sclerosis (MS) and other neuroinflammatory diseases, monocyte-derived cells (MoCs) traffic through distinct central nervous system (CNS) barriers and gain access to the organ parenchyma exerting detrimental or beneficial functions. How and where these MoCs acquire their different functional commitments during CNS invasion remains however unclear, thus hindering the design of MS treatments specifically blocking detrimental MoC actions. To clarify this issue, we investigated the distribution of iNOS+ pro-inflammatory and arginase-1+ anti-inflammatory MoCs at the distinct border regions of the CNS in a mouse model of MS. Interestingly, MoCs within perivascular parenchymal spaces displayed a predominant pro-inflammatory phenotype compared to MoCs accumulating at the leptomeninges and at the intraventricular choroid plexus (ChP). Furthermore, in an in vitro model, we could observe the general ability of functionally-polarized MoCs to migrate through the ChP epithelial barrier, together indicating the ChP as a potential CNS entry and polarization site for MoCs. Thus, pro- and anti-inflammatory MoCs differentially accumulate at distinct CNS barriers before reaching the parenchyma, but the mechanism for their phenotype acquisition remains undefined. Shedding light on this process, we observed that endothelial (BBB) and epithelial (ChP) CNS barrier cells can directly regulate transcription of Nos2 (coding for iNOS) and Arg1 (coding for arginase-1) in interacting MoCs. More specifically, while TNF-α+IFN-γ stimulated BBB cells induced Nos2 expression in MoCs, IL-1β driven activation of endothelial BBB cells led to a significant upregulation of Arg1 in MoCs. Supporting this latter finding, less pro-inflammatory MoCs could be found nearby IL1R1+ vessels in the mouse spinal cord upon neuroinflammation. Taken together, our data indicate differential distribution of pro- and anti-inflammatory MoCs at CNS borders and highlight how the interaction of MoCs with CNS barriers can significantly affect the functional activation of these CNS-invading MoCs during autoimmune inflammation.

scholarly journals Astrocyte-Derived CCL2 is Associated with M1 Activation and Recruitment of Cultured Microglial Cells

2016 ◽  
Vol 38 (3) ◽  
pp. 859-870 ◽  
Author(s):  
Mingfeng He ◽  
Hongquan Dong ◽  
Yahui Huang ◽  
Shunmei Lu ◽  
Shu Zhang ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Microglial Activation ◽  
Culture Media ◽  
Microglial Cells ◽  
Migration Ability ◽  
Migration Assay ◽  
Tnf Α

Background/Aims: Microglia are an essential player in central nervous system inflammation. Recent studies have demonstrated that the astrocytic chemokine, CCL2, is associated with microglial activation in vivo. However, CCL2-induced microglial activation has not yet been studied in vitro. The purpose of the current study was to understand the role of astrocyte-derived CCL2 in microglial activation and to elucidate the underlying mechanism(s). Methods: Primary astrocytes were pre-treated with CCL2 siRNA and stimulated with TNF-α. The culture medium (CM) was collected and added to cultures of microglia, which were incubated with and without CCR2 inhibitor. Microglial cells were analyzed by quantitative RT-PCR to determine whether they polarized to the M1 or M2 state. Microglial migratory ability was assessed by transwell migration assay. Results: TNF-α stimulated the release of CCL2 from astrocytes, even if the culture media containing TNF-α was replaced with fresh media after 3 h. CM from TNF-α-stimulated astrocytes successfully induced microglial activation, which was ascertained by increased activation of M1 and enhanced migration ability. In contrast, CM from astrocytes pretreated with CCL2 siRNA showed no effect on microglial activation, compared to controls. Additionally, microglia pre-treated with RS102895, a CCR2 inhibitor, were resistant to activation by CM from TNF-α-stimulated astrocytes. Conclusion: This study demonstrates that the CCL2/CCR2 pathway of astrocyte-induced microglial activation is associated with M1 polarization and enhanced migration ability, indicating that this pathway could be a useful target to ameliorate inflammation in the central nervous system.

scholarly journals Monocyte recruitment to the inflamed central nervous system: migration pathways and distinct functional polarization

2020 ◽  
Author(s):  
Daniela C. Ivan ◽  
Sabrina Walthert ◽  
Giuseppe Locatelli
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Choroid Plexus ◽  
Arginase 1 ◽  
Choroid Plexuses ◽  
Inflammatory Macrophages ◽  
Functional Polarization

ABSTRACTThe central nervous system (CNS) parenchyma is enclosed by anatomical interfaces including multilayered meninges, the blood-brain barrier (BBB), the choroid plexuses within ventricles and the glia limitans. These border areas hold distinct functional specializations which control the trafficking of monocyte-derived cells toward the CNS parenchyma, altogether maintaining CNS homeostasis. By crossing activated endothelial, epithelial and glial borders, circulating leukocytes gain however access to the CNS parenchyma in several inflammatory diseases including multiple sclerosis.Studies in animal models of neuroinflammation have helped describing the phenotypic specifications of these invading monocyte-derived cells, able to exert detrimental or beneficial functions depending on the local environment. In this context, in vivo visualization of iNOS+ pro-inflammatory and arginase-1+ anti-inflammatory macrophages has recently revealed that these distinct cell phenotypes are highly compartmentalized by CNS borders. While arginase-1+ macrophages densely populate the leptomeninges, iNOS+ macrophages rather accumulate in perivascular spaces and at the pia mater-CNS parenchymal interface.How and where these macrophages acquire their functional commitment, and whether differentially-activated monocyte-derived cells infiltrate the CNS through distinct gateways, remains however unclear.In this study, we have investigated the interaction of monocyte-derived macrophages with endothelial (BBB) and epithelial (choroid plexus) barriers of the CNS, both in vitro and in vivo. By using primary mouse brain microvascular endothelial cells as in vitro model of the BBB, we observed that, compared to unpolarized primary macrophages, adhesion of functionally-committed macrophages to endothelial cells was drastically reduced, literally abrogating their diapedesis across the BBB. Conversely, when interacting with an activated choroid plexus epithelium, both pro- and anti-inflammatory macrophages displayed substantial adhesive and migratory properties. Accordingly, in vivo analysis of choroid plexuses revealed increased macrophage trafficking and a scattered presence of polarized cells upon induction of anti-CNS inflammation.Altogether, we show that acquisition of distinct macrophage polarizations significantly alters the adhesive and migratory properties of these cells in a barrier-specific fashion. While monocytes trafficking at the level of the BBB seem to acquire their signature phenotype only following diapedesis, other anatomical interfaces can be the entry site for functionally activated monocyte-derived cells. Our study highlights the choroid plexus as a key access gateway for macrophages during neuroinflammation, and its stroma as a potential priming site for their functional polarization.

Curcumin loaded and co-loaded nanosystems: A review from a biological activity enhancement perspective

2020 ◽  
Vol 08 ◽  
Author(s):  
Andrea Mariela Araya-Sibaja ◽  
Krissia Wilhelm ◽  
Gustavo Adolfo González-Aguilar ◽  
José Roberto Vega-Baudrit ◽  
Norma Julieta Salazar-López ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Aqueous Solubility ◽  
Nanostructured Lipid Carrier ◽  
Protective Effects ◽  
Cell Internalization ◽  
Low Toxicity ◽  
Anti Inflammatory

Background: Curcumin is a natural phenolic compound exhibiting multiple bioactivities that have been evaluated in vitro, in vivo as well as through clinical studies in humans. Some of them include antimicrobial, antioxidant, anti-inflammatory and central nervous system protective effects. Further, curcumin is considered a Generally Recognized as Safe substance because of its low toxicity. However, its molecular structure is susceptible to changes in pH, oxidation, photodegradation, low aqueous solubility and biotransformation compromising its bioavailability, drawbacks that have been successfully addressed through nanotechnology. Objective: The present review systematizes findings on the enhancement of curcumin’s beneficial effects when it is loaded and co-loaded into different types of nanosystems covering liposomes, polymeric and solid-lipid nanoparticles, nanostructured lipid carrier, lipid-polymeric hybrids, self-assembled and protein-based core-shell systems in relation to its antimicrobial, antioxidant, anti-inflammatory and central nervous system protective bioactivities. Conclusion: Curcumin is a versatile molecule capable of exerting antimicrobial, antioxidant, anti-inflammatory and central nervous system protective effects in an enhanced manner using the possibilities offered by the nanotechnology - based approach. Its enhanced bioactivities are associated with increments in solubility, stability, bioavailability as well as in improved intracellular uptake and cell internalization. These advantages, in addition to curcumin’s low toxicity, indicate the potential of curcumin to be loaded and co-loaded into nanosystems capable to provide a controlled release and targeted administration.

scholarly journals C16, a novel sinomenine derivatives, promoted macrophage reprogramming toward M2-like phenotype and protected mice from endotoxemia

2021 ◽  
Vol 35 ◽  
pp. 205873842110267
Author(s):  
Ping Ni ◽  
Yue-Qin Liu ◽  
Jin-Yu Man ◽  
Wang Li ◽  
Shan-Shan Xue ◽  
...  
Keyword(s):  
Peritoneal Macrophages ◽  
Enzyme Linked Immunosorbent Assay ◽  
Phenotype Correlation ◽  
Arginase 1 ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Correlation Factors ◽  
M2 Phenotype

Macrophage plays a critical part in host defense, tissue repair, and anti-inflammation; Macrophage reprogramming is responsible for disease development or regression. We aimed to clarify the effect of sinomenine-4-hydroxy-palmitate (C16), on macrophage reprogramming and anti-inflammatory in endotoxemia model. According to a structure modification of SIN (Sinomenine), C16 was found. Then, based on the endotoxin model, the mice liver and kidney toxicity was evaluated and serum cytokines level of IL-6 (Interleukin-6), TNF-α (Tumor necrosis factor-α), and IL-1β (Interleukin-1β) were measured by ELISA (Enzyme linked immunosorbent assay). Then, we confirmed the effect of C16 on macrophages reprogramming, we used the flow cytometry to test the effect of C16 on macrophages apoptosis in vitro. Then, iNOS (Inducible nitric oxide synthase), M1-type related cytokines, such as IL-1β, TNF-α, and M2-type related cytokines, such as Arg-1 (Arginase-1), CD206, Fizz1, and Ym1 was detected, which expressed in ANA-1 and primary peritoneal macrophages. To further explore the molecular mechanism of C16 in reprogramming of macrophages from M1 toward M2 phenotype, the expression of STAT1 (signal transducer and activator of Transcription 1), STAT3, ERK1/2 (extracellular signal regulated kinase1/2), AKT, p38, and its corresponding phosphorylation were determined by western blot. Our results demonstrated that C16 improved the survival rate of LPS- (lipopolysaccharide) challenged mice and decreased the inflammatory cytokines expression; After C16 treatment, the expression of M1 phenotype correlation factors decreased significantly, while the expression of M2 phenotype correlation factors increased significantly at different levels compared with normal group. It indicated that C16 reprogram macrophages phenotype from M1 toward M2 following LPS stimulus. Furthermore, the results also showed that C16 showed anti-inflammatory effect by inhibiting LPS-induced p38, AKT and STAT1 phosphorylation and contributing ERK1/2 activation. C16 promoted macrophage reprogramming toward M2-like phenotype via p-p38/p-AKT or STAT1 signals pathway and C16 might be a valid candidate for inflammatory disease.

In Vivo and In Vitro Toxicodynamic Analyses of New Quinolone-and Nonsteroidal Anti-Inflammatory Drug-Induced Effects on the Central Nervous System

1999 ◽  
Vol 43 (8) ◽  
pp. 2101-2101
Author(s):  
Hideki Kita ◽  
Hirotami Matsuo ◽  
Hitomi Takanaga ◽  
Junichi Kawakami ◽  
Koujirou Yamamoto ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Drug Induced ◽  
Inflammatory Drug ◽  
The Central Nervous System ◽  
Anti Inflammatory

The central nervous system microenvironment imprints microglial inability to switch from pro- to anti-inflammatory phenotype

2014 ◽  
Vol 275 (1-2) ◽  
pp. 162
Author(s):  
Orit Matcovitch ◽  
Merav Cohen ◽  
Eyal David ◽  
Zohar Barnett-itzhaki ◽  
Hadas Keren-shaul ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Inflammatory Phenotype ◽  
The Central Nervous System ◽  
Anti Inflammatory

scholarly journals Transcriptomic Analysis of Stem Cells Treated with Moringin or Cannabidiol: Analogies and Differences in Inflammation Pathways

2019 ◽  
Vol 20 (23) ◽  
pp. 6039 ◽  
Author(s):  
Luigi Chiricosta ◽  
Serena Silvestro ◽  
Jacopo Pizzicannella ◽  
Francesca Diomede ◽  
Placido Bramanti ◽  
...  
Keyword(s):  
Stem Cells ◽  
Central Nervous System ◽  
Nervous System ◽  
Mesenchymal Stem Cells ◽  
Tnf Α ◽  
The Central Nervous System ◽  
Anti Inflammatory ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Stat Pathway

Inflammation is a common feature of many neurodegenerative diseases. The treatment of stem cells as a therapeutic approach to repair damage in the central nervous system represents a valid alternative. In this study, using Next-Generation Sequencing (NGS) technology, we analyzed the transcriptomic profile of human Gingival Mesenchymal Stem Cells (hGMSCs) treated with Moringin [4-(α-l-ramanosyloxy)-benzyl isothiocyanate] (hGMSCs-MOR) or with Cannabidiol (hGMSCs-CBD) at dose of 0.5 or 5 µM, respectively. Moreover, we compared their transcriptomic profiles in order to evaluate analogies and differences in pro- and anti-inflammatory pathways. The hGMSCs-MOR selectively downregulate TNF-α signaling from the beginning, reducing the expression of TNF-α receptor while hGMSCs-CBD limit its activity after the process started. The treatment with CBD downregulates the pro-inflammatory pathway mediated by the IL-1 family, including its receptor while MOR is less efficient. Furthermore, both the treatments are efficient in the IL-6 signaling. In particular, CBD reduces the effect of the pro-inflammatory JAK/STAT pathway while MOR enhances the pro-survival PI3K/AKT/mTOR. In addition, both hGMSCs-MOR and hGMSCs-CBD improve the anti-inflammatory activity enhancing the TGF-β pathway.

scholarly journals RAM-589.555 favors neuroprotective and anti-inflammatory profile of CNS-resident glial cells in acute relapse EAE affected mice

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Rina Zilkha-Falb ◽  
Tatyana Rachutin-Zalogin ◽  
Lakota Cleaver ◽  
Michael Gurevich ◽  
Anat Achiron
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Inflammatory Cytokines ◽  
Glial Cells ◽  
Neurotrophic Factors ◽  
Cell Mass ◽  
High Dimensional ◽  
Mass Cytometry ◽  
Anti Inflammatory

Abstract Background Targeting RNA polymerase-1 (POL1) machinery is a new strategy for suppression of multiple sclerosis (MS) relapse activity. Oral administration of POL1 inhibitor RAM-589.555, which is characterized by high permeability and bioavailability in naïve mice, ameliorates proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) by suppressing activated autoreactive lymphocytes. We assessed the accessibility of RAM-589.555 to the central nervous system (CNS) of EAE-mice and further investigated its immunomodulatory effects on CNS-resident astro- and micro-glial cells in-vitro and in-vivo. Methods Effects of RAM-589.555 on activated microglia and astrocyte viability, proliferation, and secretion of neurotrophic factors were assessed in-vitro. The pharmacokinetic of RAM-589.555 was evaluated in the blood and central nervous system (CNS) of EAE-affected mice. High-dimensional single-cell mass cytometry was applied to characterize the effect of RAM-589.555 on EAE-affected mice’s CNS-resident micro- and astroglial cells and CNS-infiltrating immune cells, which were obtained seven days after RAM-589.555 administration at EAE onset. Simultaneously, the expression level of pre-rRNA, the POL1 end product, was assessed in blood cells, microglia, and astrocytes to monitor RAM-589.555 effects. Results RAM-589.555 demonstrated blood and CNS permeability in EAE mice. In-vitro, incubation with 400 nM of RAM-589.555 significantly reduced viability and proliferation of lipopolysaccharide (LPS)-activated microglia by 70% and 45% (p < 0.05), respectively, while tumor necrosis factor α (TNFα)-activated astrocytes were not affected. The secretion of neurotrophic factors was preserved. Furthermore, 7 days after administration of RAM-589.555 at EAE onset, the level of pre-rRNA transcript in peripheral blood mononuclear cells (PBMC) was decreased by 38.6% (p = 0.02), while levels of pre-rRNA transcript in microglia and astrocytes remained unchanged. The high-dimensional single-cell mass cytometry analysis showed decreased percentages of CNS-resident microglia and astrocytes, diminished pro-inflammatory cytokines (IL-1β, IL-6, IL-12, IL-17, TNFα, and IFNγ), and an increase of their anti-inflammatory cytokines (IL-4, IL-10, and TGFβ) in RAM-589.555-treated compared to vehicle-treated mice (p < 0.05). Conclusions These data correlate RAM-589.555-induced clinical amelioration and its CNS-permeability to decreased CNS-inflammation, and decreased micro- and astrogliosis, while restoring micro- and astroglial anti-inflammatory and neuroprotective capacity.

scholarly journals IL4 Reduces Epileptogenesis Susceptibility Acutely After TBI: The Role of Macrophage/Microglia Polarization

2021 ◽  
Author(s):  
Mozhdeh Radpour ◽  
Bahar Khoshkroodian ◽  
Tara Asgari ◽  
Hamid Gholami Pourbadie ◽  
Mohammad Sayyah
Keyword(s):  
Lesion Size ◽  
Interleukin 4 ◽  
Lesion Volume ◽  
Arginase 1 ◽  
Generalized Seizures ◽  
Ptz Kindling ◽  
Tnf Α ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory ◽  
Post Traumatic Epilepsy

Abstract Traumatic brain injury (TBI) is responsible for 5% of all epilepsy cases, which are known as post-traumatic epilepsy. Macrophage/microglia are key players in TBI pathogenesis. They are activated after TBI, transform to inflammatory phenotype (M1) and trigger neuroinflammation, which provokes epileptogenesis. Interleukin-4 (IL-4) is a well-known polarizer of macrophage/microglia to the anti-inflammatory phenotype (M2). We tested the effect of IL-4 on the rate of epileptogenesis, brain expression of inflammatory and anti-inflammatory cytokines, and the lesion size in traumatic rats. Trauma was exerted to temporo-parietal cortex of rats by Controlled Cortical Impact. Thereafter, rats received a single dose (100ng/rat) of IL-4 through intracerebroventricular injection. After 24h, pentylenetetrazole (PTZ) kindling started and development of generalized seizures was recorded. Level of TNF-α, TGF-β, IL-10, and arginase-1 (Arg-1) was measured in the brain by immunoblotting at 6h, 12h, 24h, 48h, and 5 days after TBI. The lesion size and cell survival were determined by staining. Traumatic rats were kindled by 5±1 PTZ injections (significantly less than 11±2 injections of control and sham-operated rats, p<0.001). IL-4 did not change kindling rate in sham-operated rats but inhibited acceleration of kindling rate in traumatic rats (13±1 PTZ injections, p<0.001). IL-4 decreased post-TBI overexpression of TNF-α (6h, p<0.001) whereas upregulated post-TBI expression of TGF-β (48h, p<0.001), IL-10 (24h, p<0.05; 48h, p<0.01), and Arg-1 (24h, p<0.001). IL-4 decreased lesion volume and number of dead neurons. IL-4 suppresses TBI-induced acceleration of epileptogenesis in rats by directing macrophage/microglia to the anti-inflammatory M2 phenotype and inhibition of neuronal death.

Neural Stem Cells to Glial Cells an Important Factor for Brain Injury

2020 ◽  
Author(s):  
Prithiv K R Kumar
Keyword(s):  
Stem Cells ◽  
Central Nervous System ◽  
Nervous System ◽  
Neural Stem Cells ◽  
Glial Cells ◽  
Brain Injuries ◽  
The Body ◽  
The Central Nervous System ◽  
Near Future

Stem cells have the capacity to differentiate into any type of cell or organ. Stems cell originate from any part of the body, including the brain. Brain cells or rather neural stem cells have the capacitive advantage of differentiating into the central nervous system leading to the formation of neurons and glial cells. Neural stem cells should have a source by editing DNA, or by mixings chemical enzymes of iPSCs. By this method, a limitless number of neuron stem cells can be obtained. Increase in supply of NSCs help in repairing glial cells which in-turn heal the central nervous system. Generally, brain injuries cause motor and sensory deficits leading to stroke. With all trials from novel therapeutic methods to enhanced rehabilitation time, the economy and quality of life is suppressed. Only PSCs have proven effective for grafting cells into NSCs. Neurons derived from stem cells is the only challenge that limits in-vitro usage in the near future.

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