scholarly journals Microcirculatory Changes in Experimental Models of Stroke and CNS-Injury Induced Immunodepression

2019 ◽  
Vol 20 (20) ◽  
pp. 5184 ◽  
Author(s):  
Sarah Lunardi Baccetto ◽  
Christian Lehmann
Keyword(s):  
Immune Response ◽  
Cause Of Death ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Artery Occlusion ◽  
Experimental Models ◽  
Experimental Stroke ◽  
Cns Injury ◽  
Peripheral Immune Response ◽  
The Impact

Stroke is the second-leading cause of death globally and the leading cause of disability in adults. Medical complications after stroke, especially infections such as pneumonia, are the leading cause of death in stroke survivors. Systemic immunodepression is considered to contribute to increased susceptibility to infections after stroke. Different experimental models have contributed significantly to the current knowledge of stroke pathophysiology and its consequences. Each model causes different changes in the cerebral microcirculation and local inflammatory responses after ischemia. The vast majority of studies which focused on the peripheral immune response to stroke employed the middle cerebral artery occlusion method. We review various experimental stroke models with regard to microcirculatory changes and discuss the impact on local and peripheral immune response for studies of CNS-injury (central nervous system injury) induced immunodepression.

Nuclear receptor Nur77: its role in chronic inflammatory diseases

2021 ◽  
Author(s):  
Sanne C. Lith ◽  
Carlie J.M. de Vries
Keyword(s):  
Nuclear Receptor ◽  
Inflammatory Disease ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Experimental Models ◽  
Therapeutic Interventions ◽  
Alternative Mechanism ◽  
Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

Abstract P746: Sex Differences in Cognitive and Psychological Outcomes of Stroke: Impact of Diabetes

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Victoria L Wolf ◽  
Aunay Miller ◽  
Raghavendar Chandran ◽  
Weiguo Li ◽  
Adviye Ergul
Keyword(s):  
Artery Occlusion ◽  
Psychological Outcomes ◽  
Experimental Stroke ◽  
Dark Light ◽  
Stroke Outcomes ◽  
Post Stroke ◽  
Stroke Research ◽  
Y Maze ◽  
Male Animal ◽  
The Impact

Diabetes increases risk and severity of post-stroke cognitive impairment (PSCI), a major cause of disability worldwide. While it is known that females suffer more from PSCI, psychological outcomes and underlying reasons are poorly understood. From a preclinical perspective, potential explanations include 1) use of otherwise healthy animals in experimental stroke research without integration of common comorbid diseases like diabetes into the study design, and 2) optimization of most behavioral tests for sensorimotor and cognitive functions using only male animal models. Our hypothesis is that post-stroke outcomes are sex and comorbid disease-dependent. To test this, we validated the Novel Object Recognition (NOR), Y-maze, and Passive Avoidance (PAT) behavioral paradigms in Ctrl and Diabetic (DM) male (M) and female (F) rats pre- and post-stroke (S) via 60 min. middle cerebral artery occlusion (MCAO). We tested the PAT paradigm with a multi-trial method where the animals were habituated to the dark/light chambers without foot shock and then trained in 3 trials where they received foot shock upon entering the dark. We then tested retention following MCAO for their memory of foot shock 2 weeks prior. Multitrial results suggested that there was no difference between groups in learning to associate the dark chamber with the shock, so we revised the multitrial method into a single-trial method for ongoing retention tests to compare the impact of stroke on shock memory recall. PAT revealed (Table 1) disease- and sex-dependent responses to aversive stimulus. NOR revealed that M-DM-S and F-DM-S rats have decreased exploration time, suggesting that they are unmotivated or depressed. Y-maze indicated that males displayed spatial memory recovery, while females remained impaired. In summary, we have observed numerous sex- and disease-dependent post-stroke outcomes with standard behavioral paradigms, causing us to carefully consider how we evaluate preclinical outcomes.

scholarly journals Microglia: Agents of the CNS Pro-Inflammatory Response

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1717 ◽  
Author(s):  
José A. Rodríguez-Gómez ◽  
Edel Kavanagh ◽  
Pinelopi Engskog-Vlachos ◽  
Mikael K.R. Engskog ◽  
Antonio J. Herrera ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Neurodegenerative Diseases ◽  
Current Knowledge ◽  
Reactive Microglia ◽  
Holistic View ◽  
Human Microglia ◽  
Positron Emission ◽  
New Research ◽  
The Impact

The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.

scholarly journals Skin Immunity to Dermatophytes: From Experimental Infection Models to Human Disease

2020 ◽  
Vol 11 ◽  
Author(s):  
Verónica L. Burstein ◽  
Ignacio Beccacece ◽  
Lorena Guasconi ◽  
Cristian J. Mena ◽  
Laura Cervi ◽  
...  
Keyword(s):  
Immune Response ◽  
Human Disease ◽  
Current Knowledge ◽  
Skin Inflammation ◽  
Experimental Models ◽  
Fungal Virulence ◽  
Lectin Receptors ◽  
Immunological Mechanisms ◽  
Human Infections ◽  
Cellular Immune

Dermatophytoses (ringworms) are among the most frequent skin infections and are a highly prevalent cause of human disease worldwide. Despite the incidence of these superficial mycoses in healthy people and the compelling evidence on chronic and deep infections in immunocompromised individuals, the mechanisms controlling dermatophyte invasion in the skin are scarcely known. In the last years, the association between certain primary immunodeficiencies and the susceptibility to severe dermatophytosis as well as the evidence provided by novel experimental models mimicking human disease have significantly contributed to deciphering the basic immunological mechanisms against dermatophytes. In this review, we outline the current knowledge on fungal virulence factors involved in the pathogenesis of dermatophytoses and recent evidence from human infections and experimental models that shed light on the cells and molecules involved in the antifungal cutaneous immune response. The latest highlights emphasize the contribution of C-type lectin receptors signaling and the cellular immune response mediated by IL-17 and IFN-γ in the anti-dermatophytic defense and skin inflammation control.

scholarly journals Impact of Key Nicotinic AChR Subunits on Post-Stroke Pneumococcal Pneumonia

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 253
Author(s):  
Sandra Jagdmann ◽  
Claudia Dames ◽  
Daniel Berchtold ◽  
Katarzyna Winek ◽  
Luis Weitbrecht ◽  
...  
Keyword(s):  
Artery Occlusion ◽  
Experimental Stroke ◽  
Medical Complication ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Post Stroke ◽  
Cholinergic Signaling ◽  
Cerebral Artery Occlusion ◽  
Pathogen Clearance ◽  
The Impact ◽  
Alveolar Capillary

Pneumonia is the most frequent severe medical complication after stroke. An overactivation of the cholinergic signaling after stroke contributes to immunosuppression and the development of spontaneous pneumonia caused by Gram-negative pathogens. The α7 nicotinic acetylcholine receptor (α7nAChR) has already been identified as an important mediator of the anti-inflammatory pathway after stroke. However, whether the α2, α5 and α9/10 nAChR expressed in the lung also play a role in suppression of pulmonary innate immunity after stroke is unknown. In the present study, we investigate the impact of various nAChRs on aspiration-induced pneumonia after stroke. Therefore, α2, α5, α7 and α9/10 nAChR knockout (KO) mice and wild type (WT) littermates were infected with Streptococcus pneumoniae (S. pneumoniae) three days after middle cerebral artery occlusion (MCAo). One day after infection pathogen clearance, cellularity in lung and spleen, cytokine secretion in bronchoalveolar lavage (BAL) and alveolar-capillary barrier were investigated. Here, we found that deficiency of various nAChRs does not contribute to an enhanced clearance of a Gram-positive pathogen causing post-stroke pneumonia in mice. In conclusion, these findings suggest that a single nAChR is not sufficient to mediate the impaired pulmonary defense against S. pneumoniae after experimental stroke.

scholarly journals Anti-Inflammatory Effects of the 70 kDa Heat Shock Protein in Experimental Stroke

2007 ◽  
Vol 28 (1) ◽  
pp. 53-63 ◽  
Author(s):  
Zhen Zheng ◽  
Jong Youl Kim ◽  
Hualong Ma ◽  
Jong Eun Lee ◽  
Midori A Yenari
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Brain Ischemia ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Artery Occlusion ◽  
Brain Inflammation ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Anti Inflammatory

The 70-kDa heat shock protein (Hsp70) is involved in protecting the brain from a variety of insults including stroke. Although the mechanism has been largely considered to be because of its chaperone functions, recent work indicates that Hsp70 also modulates inflammatory responses. To explore how and whether Hsp70 regulate immune responses in brain ischemia, mice overexpressing Hsp70 (Hsp Tg) were subjected to 2 h middle cerebral artery occlusion, followed by 24 h reperfusion. Parallel experiments were performed using a brain inflammation model. Hsp Tg microglia cocultured with astrocytes were used to evaluate the direct effects of Hsp70 on cytotoxicity of mcrigolia. Compared with wild-type (Wt) littermates, Hsp Tg mice showed decreased infarct size and improved neurological deficits. The number of activated microglia/macrophages were also reduced in ischemic brains of Hsp Tg mice. Similar observations were made in a model of brain inflammation that does not result in brain cell death. Overexpression of Hsp70 in microglia completely prevented microglia-induced cytotoxicity to astrocytes. Activation of the inflammatory transcription factor, nuclear factor-κB (NF-κB) was inhibited significantly in Hsp Tg mice and microglia. This was associated with decreased phosphorylation of NF-κB inhibitor protein, IκBα, and decreased expression of several NFκB-regulated genes. Co-immunoprecipitation studies revealed an interaction of Hsp70 with NF-κB and IκBα, but not with IkB kinase, IKKγ, suggesting that Hsp70 binds to the NF-κB:IκB complex preventing IκB phosphorylation by IKK. The findings of the present work establish an anti-inflammatory role for Hsp70 in the context of brain ischemia as a novel mechanism of protection.

scholarly journals Effects of Lactobacillus plantarum and Lactobacillus paracasei on the Peripheral Immune Response in Children with Celiac Disease Autoimmunity: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Nutrients ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1925 ◽  
Author(s):  
Åsa Håkansson ◽  
Carin Andrén Aronsson ◽  
Charlotte Brundin ◽  
Elin Oscarsson ◽  
Göran Molin ◽  
...  
Keyword(s):  
Immune Response ◽  
Celiac Disease ◽  
Placebo Group ◽  
Inflammatory Responses ◽  
Tissue Transglutaminase ◽  
Controlled Clinical Trial ◽  
Double Blind ◽  
Th Cells ◽  
Double Blind Placebo ◽  
Peripheral Immune Response

Two Lactobacillus strains have proven anti-inflammatory properties by reducing pro-inflammatory responses to antigens. This randomized double-blind placebo-controlled trial tested the hypothesis that L. plantarum HEAL9 and L. paracasei 8700:2 suppress ongoing celiac disease autoimmunity in genetically at risk children on a gluten-containing diet in a longitudinally screening study for celiac disease. Seventy-eight children with celiac disease autoimmunity participated of whom 40 received 1010 CFU/day of L. plantarum HEAL9 and L. paracasei 8700:2 (probiotic group) and 38 children maltodextrin (placebo group) for six months. Blood samples were drawn at zero, three and six months and phenotyping of peripheral blood lymphocytes and IgA and IgG autoantibodies against tissue transglutaminase (tTG) were measured. In the placebo group, naïve CD45RA+ Th cells decreased (p = 0.002) whereas effector and memory CD45RO+ Th cells increased (p = 0.003). In contrast, populations of cells expressing CD4+CD25highCD45RO+CCR4+ increased in the placebo group (p = 0.001). Changes between the groups were observed for NK cells (p = 0.038) and NKT cells (p = 0.008). Median levels of IgA-tTG decreased more significantly over time in the probiotic (p = 0.013) than in the placebo (p = 0.043) group whereas the opposite was true for IgG-tTG (p = 0.062 respective p = 0.008). In conclusion, daily oral administration of L. plantarum HEAL9 and L. paracasei 8700:2 modulate the peripheral immune response in children with celiac disease autoimmunity.

Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes

2015 ◽  
Vol 114 (09) ◽  
pp. 478-789 ◽  
Author(s):  
Waltraud Schrottmaier ◽  
Julia Kral ◽  
Sigrun Badrnya ◽  
Alice Assinger
Keyword(s):  
Immune Responses ◽  
Antiplatelet Therapy ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cardiovascular Complications ◽  
P2y12 Inhibitors ◽  
Beneficial Effects ◽  
Cox Inhibitor ◽  
The Impact

SummaryPlatelets are key players in haemostasis and represent a pivotal link between inflammation, immunity and atherogenesis. Depending on the (patho)physiological environment platelets modulate various leukocyte functions via release of inflammatory mediators and direct cell-cell interactions. Elevated levels of circulating platelet-leukocyte aggregates are found in patients suffering from several thrombotic or inflammatory conditions. Platelet-monocyte and platelet-neutrophil interaction can trigger pro- and anti-inflammatory responses and modulate effector functions of all leukocyte subpopulations. These platelet-mediated immune responses have implications for the progression of cardiovascular diseases and also play a crucial role during infections, cancer, transplantations and other inflammatory diseases of several organs. Antiplatelet therapy including the COX inhibitor aspirin and/or ADP receptor P2Y12 inhibitors such as clopidogrel, prasugrel and ticagrelor are the therapy of choice for various cardiovascular complications. Both aspirin and P2Y12 inhibitors attenuate platelet-leukocyte interactions, thereby also modulating immune responses. This may have beneficial effects in some pathological conditions, while it might be detrimental in others. This review aims to summarise the current knowledge on platelet-leukocyte interactions and the impact of aspirin and P2Y12 inhibition on platelet-mediated immune responses and to give an overview on the effects of antiplatelet therapy on platelet-leukocyte interplay in various diseases.

scholarly journals Selective Liposomal Transport Through Blood Brain Barrier Disruption in Ischaemic Stroke Reveals Two Distinct Therapeutic Opportunities

2019 ◽  
Author(s):  
Zahraa S. Al-Ahmady ◽  
Dhifaf Jasim ◽  
Sabahuddin Syed Ahmad ◽  
Raymond Wong ◽  
Michael Haley ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Inflammatory Responses ◽  
Neurovascular Unit ◽  
Artery Occlusion ◽  
Brain Barrier ◽  
Experimental Stroke ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Ischaemic Brain

AbstractThe development of new therapies for stroke continues to face repeated translational failures. Brain endothelial cells form paracellular and transcellular barriers to many blood-borne therapies and the development of efficient delivery strategies is highly warranted. Here, in a mouse model of stroke, we show selective recruitment of clinically used liposomes into the ischaemic brain that correlates with biphasic blood brain barrier (BBB) breakdown. Intravenous administration of liposomes into mice exposed to transient middle cerebral artery occlusion took place at early (0.5h and 4h) and delayed (24h and 48h) timepoints, covering different phases of BBB disruption after stroke. Using a combination of in vivo real-time imaging and histological analysis we show that selective liposomal brain accumulation coincides with biphasic enhancement in transcellular transport followed by a delayed impairment to the paracellular barrier. This process precedes neurological damage in the acute phase and maintains long-term liposomal co-localisation within the neurovascular unit, which could have great potential for neuroprotection. Levels of liposomal uptake by glial cells are similarly selectively enhanced in the ischaemic region late after experimental stroke (2-3 days), highlighting their potential for blocking delayed inflammatory responses or shifting the polarization of microglia/macrophages towards brain repair.These findings demonstrate the capability of liposomes to maximise selective translocation into the brain after stroke and identify for the first time two windows for therapeutic manipulation. This emphasizes the benefits of selective drug delivery for efficient tailoring of new stroke treatments.

scholarly journals Redox Regulation of STAT1 and STAT3 Signaling

2020 ◽  
Vol 21 (19) ◽  
pp. 7034
Author(s):  
Elena Butturini ◽  
Alessandra Carcereri de Prati ◽  
Sofia Mariotto
Keyword(s):  
Cell Cycle ◽  
Immune Response ◽  
Cell Death ◽  
Redox Regulation ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Apoptotic Cell ◽  
Post Translational Modifications ◽  
Environmental Signals ◽  
Stat3 Signaling

STAT1 and STAT3 are nuclear transcription factors that regulate genes involved in cell cycle, cell survival and immune response. The cross-talk between these signaling pathways determines how cells integrate the environmental signals received ultimately translating them in transcriptional regulation of specific sets of genes. Despite being activated downstream of common cytokine and growth factors, STAT1 and STAT3 play essentially antagonistic roles and the disruption of their balance directs cells from survival to apoptotic cell death or from inflammatory to anti-inflammatory responses. Different mechanisms are proposed to explain this yin-yang relationship. Considering the redox aspect of STATs proteins, this review attempts to summarize the current knowledge of redox regulation of STAT1 and STAT3 signaling focusing the attention on the post-translational modifications that affect their activity.

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