scholarly journals Longitudinal transcriptomics define the stages of myeloid activation in the living human brain after intracerebral hemorrhage

2021 ◽  
Vol 6 (56) ◽  
pp. eabd6279
Author(s):  
Michael H. Askenase ◽  
Brittany A. Goods ◽  
Hannah E. Beatty ◽  
Arthur F. Steinschneider ◽  
Sofia E. Velazquez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Injury ◽  
Immune Responses ◽  
Intracerebral Hemorrhage ◽  
Human Brain ◽  
Inflammatory Factors ◽  
Lipid Mediator ◽  
Prostaglandin E ◽  
Anti Inflammatory ◽  
Over Time

Opportunities to interrogate the immune responses in the injured tissue of living patients suffering from acute sterile injuries such as stroke and heart attack are limited. We leveraged a clinical trial of minimally invasive neurosurgery for patients with intracerebral hemorrhage (ICH), a severely disabling subtype of stroke, to investigate the dynamics of inflammation at the site of brain injury over time. Longitudinal transcriptional profiling of CD14+ monocytes/macrophages and neutrophils from hematomas of patients with ICH revealed that the myeloid response to ICH within the hematoma is distinct from that in the blood and occurs in stages conserved across the patient cohort. Initially, hematoma myeloid cells expressed a robust anabolic proinflammatory profile characterized by activation of hypoxia-inducible factors (HIFs) and expression of genes encoding immune factors and glycolysis. Subsequently, inflammatory gene expression decreased over time, whereas anti-inflammatory circuits were maintained and phagocytic and antioxidative pathways up-regulated. During this transition to immune resolution, glycolysis gene expression and levels of the potent proresolution lipid mediator prostaglandin E2 remained elevated in the hematoma, and unexpectedly, these elevations correlated with positive patient outcomes. Ex vivo activation of human macrophages by ICH-associated stimuli highlighted an important role for HIFs in production of both inflammatory and anti-inflammatory factors, including PGE2, which, in turn, augmented VEGF production. Our findings define the time course of myeloid activation in the human brain after ICH, revealing a conserved progression of immune responses from proinflammatory to proresolution states in humans after brain injury and identifying transcriptional programs associated with neurological recovery.

Abstract TP99: Human Lung Endothelial Cell Anti-Inflammatory and Regenerative Responses in Acute Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Nikunj Satani ◽  
Kaavya Giridhar ◽  
Natalia Wewior ◽  
Dominique D Norris ◽  
Scott D Olson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Inflammatory Responses ◽  
Inflammatory Factors ◽  
Stroke Severity ◽  
Stroke Patients ◽  
Anti Inflammatory ◽  
Lung Endothelial Cells ◽  
Stroke Mimic

Background: Inflammatory responses after stroke consists of central and peripheral immune responses. The role of the spleen after stroke is well-known, however the role of the lungs has not been studied in detail. We explored the relation between stroke severity and immunomodulatory changes in lung endothelial cells. Methods: Human pulmonary endothelial cells (hPECs, Cell Biologics) were cultured at passage 3. Serum from stroke patients with NIH Stroke Scale (NIHSS) severity ranging from 0 to 20 was collected at 24 hours after stroke. hPECs were exposed to media with 1) 10% FBS alone (N=6), 2) 10% serum from stroke patients (N=72), or 3) 10% serum from stroke mimic patients (N=6). After 3 hour of exposure, fresh media was added and secretomes from hPECs were measured after 24 hours. We isolated RNA from hPECs after 3 hour of serum exposure and measured gene expression (N=6 for each group). Secretome and gene changes in hPECs were analyzed based on stroke severity, tPA treatment, and co-morbidities. Results: Serum from stroke patients reduced the secretion of IL-8, MCP-1 and Fractalkine (p<0.01), and increased the secretion of VEGF and BDNF (p<0.01) from hPECs. These effects were more pronounced depending on stroke severity (Fig). There was no effect of tPA or T2DM on hPECs secretomes. There was significantly reduced gene expression of IL-6, IL-8, MCP-1 and IL-1β and significantly higher expression of ICAM1, IGF-1 and TGF-β1 as compared to stroke mimics. Conclusion: Exposure of hPECs to serum from stroke patients alters their immunomodulatory properties. Higher severity of stroke leads to more protective response from hPECs by reducing the secretion of pro-inflammatory factors, while increasing the secretion of anti-inflammatory factors.

scholarly journals Anti-Inflammatory Effects of Fucoxanthinol in LPS-Induced RAW264.7 Cells through the NAAA-PEA Pathway

Marine Drugs ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 222 ◽  
Author(s):  
Wenhui Jin ◽  
Longhe Yang ◽  
Zhiwei Yi ◽  
Hua Fang ◽  
Weizhu Chen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Inhibitory Effect ◽  
Inflammatory Factors ◽  
Lipid Mediator ◽  
Peroxisome Proliferator ◽  
Necrosis Factor Alpha ◽  
Peroxisome Proliferator Activated Receptor ◽  
Tnf Α ◽  
Anti Inflammatory

Palmitoylethanolamide (PEA) is an endogenous lipid mediator with powerful anti-inflammatory and analgesic functions. PEA can be hydrolyzed by a lysosomal enzyme N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages and other immune cells. The pharmacological inhibition of NAAA activity is a potential therapeutic strategy for inflammation-related diseases. Fucoxanthinol (FXOH) is a marine carotenoid from brown seaweeds with various beneficial effects. However, the anti-inflammatory effects and mechanism of action of FXOH in lipopolysaccharide (LPS)-stimulated macrophages remain unclear. This study aimed to explore the role of FXOH in the NAAA–PEA pathway and the anti-inflammatory effects based on this mechanism. In vitro results showed that FXOH can directly bind to the active site of NAAA protein and specifically inhibit the activity of NAAA enzyme. In an LPS-induced inflammatory model in macrophages, FXOH pretreatment significantly reversed the LPS-induced downregulation of PEA levels. FXOH also substantially attenuated the mRNA expression of inflammatory factors, including inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and markedly reduced the production of TNF-α, IL-6, IL-1β, and nitric oxide (NO). Moreover, the inhibitory effect of FXOH on NO induction was significantly abolished by the peroxisome proliferator-activated receptor α (PPAR-α) inhibitor GW6471. All these findings demonstrated that FXOH can prevent LPS-induced inflammation in macrophages, and its mechanisms may be associated with the regulation of the NAAA-PEA-PPAR-α pathway.

scholarly journals Fumaric Acids Directly Influence Gene Expression of Neuroprotective Factors in Rodent Microglia

2019 ◽  
Vol 20 (2) ◽  
pp. 325 ◽  
Author(s):  
Jessica Kronenberg ◽  
Kaweh Pars ◽  
Marina Brieskorn ◽  
Chittappen Prajeeth ◽  
Sandra Heckers ◽  
...  
Keyword(s):  
Gene Expression ◽  
Indirect Effects ◽  
Protein Level ◽  
Mannose Receptor ◽  
Inflammatory Factors ◽  
Primary Metabolite ◽  
Proliferation And Differentiation ◽  
Anti Inflammatory ◽  
Relapsing Remitting Multiple Sclerosis

Dimethylfumarate (DMF) has been approved the for treatment of relapsing-remitting multiple sclerosis. The mode of action of DMF and its assumed active primary metabolite monomethylfumarate (MMF) is still not fully understood, notably for brain resident cells. Therefore we investigated potential direct effects of DMF and MMF on microglia and indirect effects on oligodendrocytes. Primary rat microglia were differentiated into M1-like, M2-like and M0 phenotypes and treated in vitro with DMF or MMF. The gene expression of pro-inflammatory and anti-inflammatory factors such as growth factors (IGF-1), interleukins (IL-10, IL-1β), chemokines (CCl3, CXCL-10) as well as cytokines (TGF-1β, TNFα), iNOS, and the mannose receptor (MRC1) was examined by determining their transcription level with qPCR, and on the protein level by ELISA and FACS analysis. Furthermore, microglia function was determined by phagocytosis assays and indirect effects on oligodendroglial proliferation and differentiation. DMF treatment of M0 and M1-like polarized microglia demonstrated an upregulation of gene expression for IGF-1 and MRC1, but not on the protein level. While the phagocytic activity remained unchanged, DMF and MMF treated microglia supernatants led to an enhanced proliferation of oligodendrocyte precursor cells (OPC). These results suggest that DMF has anti-inflammatory effects on microglia which may result in enhanced proliferation of OPC.

Death receptors on reactive astrocytes

Neurology ◽  
2003 ◽  
Vol 60 (4) ◽  
pp. 548-554 ◽  
Author(s):  
Pierre-Yves Dietrich ◽  
Paul R. Walker ◽  
Philippe Saas
Keyword(s):  
Brain Injury ◽  
Immune Responses ◽  
Death Receptors ◽  
Reactive Astrocytes ◽  
Brain Inflammation ◽  
Fine Tuning ◽  
Immune Mediated ◽  
Anti Inflammatory ◽  
The Brain

Immune responses protect the CNS against pathogens. However, the fact that there is little dispensable tissue in the brain makes regulation necessary to avoid disastrous immune-mediated damage. Astrocytes respond vigorously to any brain injury (e.g., tumor, stroke, AD, MS, HIV) and are postulated to play an important role in the fine tuning of brain inflammation. The authors propose that astrocytes use death receptors to modulate pro- and anti-inflammatory effects.

scholarly journals Non-Genetic Reprogramming of Monocytes via Microparticle Phagocytosis for Sustained Modulation of Macrophage Phenotype

2019 ◽  
Author(s):  
Kathryn L. Wofford ◽  
Bhavani S. Singh ◽  
D. Kacy Cullen ◽  
Kara L. Spiller
Keyword(s):  
Cell Therapy ◽  
Inflammatory Factors ◽  
Macrophage Phenotype ◽  
Vast Number ◽  
Inflammatory Drug ◽  
Rapid Acquisition ◽  
Therapy Strategy ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory ◽  
Over Time

ABSTRACTMonocyte-derived macrophages orchestrate tissue regeneration by homing to sites of injury, phagocytosing pathological debris, and stimulating other cell types to repair the tissue. Accordingly, monocytes have been investigated as a translational and potent source for cell therapy, but their utility has been hampered by their rapid acquisition of a pro-inflammatory phenotype in response to the inflammatory injury microenvironment. To overcome this problem, we designed a cell therapy strategy where we collect and exogenously reprogram monocytes by intracellularly loading the cells with biodegradable microparticles containing an anti-inflammatory drug in order to modulate and maintain an anti-inflammatory phenotype over time. To test this concept, poly(lactic-co-glycolic) acid microparticles were loaded with the anti-inflammatory drug dexamethasone (Dex) and administered to primary human monocytes for four hours to facilitate phagocytic uptake. After removal of non-phagocytosed microparticles, microparticle-loaded monocytes differentiated into macrophages and stored the microparticles intracellularly for several weeks in vitro, releasing drug into the extracellular environment over time. Cells loaded with intracellular Dex microparticles showed decreased expression and secretion of inflammatory factors even in the presence of pro-inflammatory stimuli up to 7 days after microparticle uptake compared to untreated cells or cells loaded with blank microparticles. This study represents a new strategy for long-term maintenance of anti-inflammatory macrophage phenotype using a translational monocyte-based cell therapy strategy without the use of genetic modification. Because of the ubiquitous nature of monocyte-derived macrophage involvement in pathology and regeneration, this strategy holds potential as a treatment for a vast number of diseases and disorders.

Cerebral Palsy

2017 ◽  
Author(s):  
Joan M. Jasien ◽  
Bruce K. Shapiro ◽  
Alexander H. Hoon
Keyword(s):  
Cerebral Palsy ◽  
Brain Injury ◽  
Human Brain ◽  
Selective Vulnerability ◽  
Postnatal Life ◽  
Organizational Changes ◽  
Immature Brain ◽  
The Brain ◽  
Compensatory Plasticity ◽  
Over Time

Cerebral palsy (CP) describes a group of disorders of movement/posture causing activity limitation that are attributed to nonprogressive disturbances in the immature brain that can change over time. The immature human brain undergoes organizational changes during intrauterine and postnatal life creating potential temporal periods of selective vulnerability to damage. Understanding the compensatory plasticity process after the brain injury may provide new insights into the pathogenesis of CP.

scholarly journals TT-301 Inhibits Microglial Activation and Improves Outcome after Central Nervous System Injury in Adult Mice

2012 ◽  
Vol 116 (6) ◽  
pp. 1299-1311 ◽  
Author(s):  
Michael L. James ◽  
Haichen Wang ◽  
Viviana Cantillana ◽  
Beilei Lei ◽  
Dawn N. Kernagis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Functional Outcome ◽  
Differential Gene Expression ◽  
Morris Water Maze ◽  
Water Maze ◽  
Murine Models ◽  
Differential Gene

Background Microglial inhibition may reduce secondary tissue injury and improve functional outcome following acute brain injury. Utilizing clinically relevant murine models of traumatic brain injury and intracerebral hemorrhage, neuroinflammatory responses and functional outcome were examined in the presence of a potential microglial inhibitor, TT-301. Methods TT-301 or saline was administered following traumatic brain injury or intracerebral hemorrhage, and then for four subsequent days. The effect of TT-301 on neuroinflammatory responses and neuronal viability was assessed, as well as short-term vestibulomotor deficit (Rotorod) and long-term neurocognitive impairment (Morris water maze). Finally differential gene expression profiles of mice treated with TT-301 were compared with those of vehicle. Results Reduction in F4/80+ staining was demonstrated at 1 and 10 days, but not 28 days, after injury in mice treated with TT-301 (n = 6). These histologic findings were associated with improved neurologic function as assessed by Rotorod, which improved by 52.7% in the treated group by day 7, and Morris water maze latencies, which improved by 232.5% as a function of treatment (n = 12; P &lt; 0.05). Similar benefit was demonstrated following intracerebral hemorrhage, in which treatment with TT-301 was associated with functional neurologic improvement of 39.6% improvement in Rotorod and a reduction in cerebral edema that was independent of hematoma volume (n = 12; P &lt; 0.05). Differential gene expression was evaluated following treatment with TT-301, and hierarchical cluster analysis implicated involvement of the Janus kinase-Signal Transducer and Activator of Transcription pathway after administration of TT-301 (n = 3/group). Conclusions Modulation of neuroinflammatory responses through TT-301 administration improved histologic and functional parameters in murine models of acute neurologic injury.

PSXV-17 Dietary postbiotic mediates cytokine gene expression in senior horses

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 360-361
Author(s):  
Sharon A Norton ◽  
Amanda A Adams
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Mixed Model ◽  
Body Condition Score ◽  
Animal Health ◽  
Cytokine Gene Expression ◽  
Cytokine Gene ◽  
Tnf Α ◽  
Cox 2 ◽  
Over Time

Abstract Senior horses often exhibit chronic inflammation and decreased immune responses. Dietary Saccharomyces cerevisiae fermentation product (SCFP; Diamond V, Cedar Rapids, IA) has been shown to affect immune responses in several species. This study aimed to evaluate SCFP-mediated immune function in senior horses. Sixteen horses (24.8 ± 3.0 y; BW = 545.8 ± 61.9 kg) were allotted to two treatments: CON (n = 8; no SCFP supplementation) and SCFP top dressed onto a common concentrate for 56 d (21 g/d; n = 8). Body condition score (BCS), BW, whole blood cytokine (INF-ɣ, TNF-α, IL-1β, IL-6, IL-10, IL-4, IL-8, IL-13, IL-17) and COX-1 and COX-2 gene expression were measured at d 0, 42, 49 and 56. Horses were challenged with a monovalent influenza vaccine at d 42 (MIV; Fluvacc Innovator; Zoetis Animal Health, Parsippany, NJ). Pre-MIV (d 0–42) and post-MIV (d 42–56) responses were analyzed using general mixed model procedures. Pre-MIV, BW tended to increase (P = 0.09) over time. Expression of IL-10 tended to be lower for SCFP than CON (P = 0.09) and IL-13 expression decreased over time (P &lt; 0.05). Post-MIV, BCS linearly increased over time (P = 0.006) while TNF-α tended to increase at d 49 and return to d 42 levels by d 56 (P = 0.06). Both INF-ɣ and IL-10 expression were lower for SCFP vs CON (P &lt; 0.05). Gene expression of COX-2 tended to decrease (P = 0.06) at d 49 and return to the d 42 baseline by d 56. Gene expression of IL-13 tended to decrease with SCFP but increased with CON at d 49 with both returning to d 42 levels by d 56 (P = 0.08). Influenza H1 titers increased over time post-vaccination (P &lt; 0.001) with no difference between treatments. Dietary SCFP may modulate pro-inflammatory and anti-inflammatory cytokine gene expression in senior horses.

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