scholarly journals Transfer RNA fragments replace microRNA regulators of the cholinergic post-stroke immune blockade

2020 ◽  
Author(s):  
Katarzyna Winek ◽  
Sebastian Lobentanzer ◽  
Bettina Nadorp ◽  
Serafima Dubnov ◽  
Claudia Dames ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Immune Responses ◽  
Small Rna ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Transfer Rna ◽  
Raw 264.7 Cells ◽  
Post Stroke ◽  
Susceptibility To Infection ◽  
Rna Fragments

AbstractStroke is a leading cause of death and disability. Recovery depends on a delicate balance between inflammatory responses and immune suppression, tipping the scale between brain protection and susceptibility to infection. Peripheral cholinergic blockade of immune reactions fine-tunes this immune response, but its molecular regulators are unknown. Here, we report a regulatory shift in small RNA types in patient blood sequenced two days after ischemic stroke, comprising massive decreases of microRNA levels and concomitant increases of transfer RNA fragments (tRFs) targeting cholinergic transcripts. Electrophoresis-based size-selection followed by RT-qPCR validated the top 6 upregulated tRFs in a separate cohort of stroke patients, and independent datasets of small and long RNA sequencing pinpointed immune cell subsets pivotal to these responses, implicating CD14+ monocytes in the cholinergic inflammatory reflex. In-depth small RNA targeting analyses revealed the most-perturbed pathways following stroke and implied a structural dichotomy between microRNA and tRF target sets. Furthermore, lipopolysaccharide stimulation of murine RAW 264.7 cells and human CD14+ monocytes upregulated the top 6 stroke-perturbed tRFs, and overexpression of stroke-inducible tRF-22-WE8SPOX52 using an ssRNA mimic induced downregulation of immune regulator Z-DNA binding protein 1 (Zbp1). In summary, we identified a “changing of the guards” between RNA types that may systemically affect homeostasis in post-stroke immune responses, and pinpointed multiple affected pathways, which opens new venues for establishing therapeutics and biomarkers at the protein- and RNA-level.Significance StatementIschemic stroke triggers peripheral immunosuppression, increasing the susceptibility to post-stroke pneumonia that is linked with poor survival. The post-stroke brain initiates intensive communication with the immune system, and acetylcholine contributes to these messages; but the responsible molecules are yet unknown. We discovered a “changing of the guards,” where microRNA levels decreased but small transfer RNA fragments (tRFs) increased in post-stroke blood. This molecular switch may re-balance acetylcholine signaling in CD14+ monocytes by regulating their gene expression and modulating post-stroke immunity. Our observations point out to tRFs as molecular regulators of post-stroke immune responses that may be potential therapeutic targets.

scholarly journals Transfer RNA fragments replace microRNA regulators of the cholinergic poststroke immune blockade

2020 ◽  
Vol 117 (51) ◽  
pp. 32606-32616
Author(s):  
Katarzyna Winek ◽  
Sebastian Lobentanzer ◽  
Bettina Nadorp ◽  
Serafima Dubnov ◽  
Claudia Dames ◽  
...  
Keyword(s):  
Small Rna ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Transfer Rna ◽  
Raw 264.7 Cells ◽  
Susceptibility To Infection ◽  
Immune Cell Subsets ◽  
Rna Targeting ◽  
Rna Fragments ◽  
Separate Cohort

Stroke is a leading cause of death and disability. Recovery depends on a delicate balance between inflammatory responses and immune suppression, tipping the scale between brain protection and susceptibility to infection. Peripheral cholinergic blockade of immune reactions fine-tunes this immune response, but its molecular regulators are unknown. Here, we report a regulatory shift in small RNA types in patient blood sequenced 2 d after ischemic stroke, comprising massive decreases of microRNA levels and concomitant increases of transfer RNA fragments (tRFs) targeting cholinergic transcripts. Electrophoresis-based size-selection followed by qRT-PCR validated the top six up-regulated tRFs in a separate cohort of stroke patients, and independent datasets of small and long RNA sequencing pinpointed immune cell subsets pivotal to these responses, implicating CD14+monocytes in the cholinergic inflammatory reflex. In-depth small RNA targeting analyses revealed the most-perturbed pathways following stroke and implied a structural dichotomy between microRNA and tRF target sets. Furthermore, lipopolysaccharide stimulation of murine RAW 264.7 cells and human CD14+monocytes up-regulated the top six stroke-perturbed tRFs, and overexpression of stroke-inducible tRF-22-WE8SPOX52 using a single-stranded RNA mimic induced down-regulation of immune regulator Z-DNA binding protein 1. In summary, we identified a “changing of the guards” between small RNA types that may systemically affect homeostasis in poststroke immune responses, and pinpointed multiple affected pathways, which opens new venues for establishing therapeutics and biomarkers at the protein and RNA level.

scholarly journals A Missing Link: Engagements of Dendritic Cells in the Pathogenesis of SARS-CoV-2 Infections

2021 ◽  
Vol 22 (3) ◽  
pp. 1118
Author(s):  
Abdulaziz Alamri ◽  
Derek Fisk ◽  
Deepak Upreti ◽  
Sam K. P. Kung
Keyword(s):  
Dendritic Cells ◽  
Severe Acute Respiratory Syndrome ◽  
Immune Responses ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Viral Disease ◽  
Cell Recruitment ◽  
Cross Presentation ◽  
Cell Immunity ◽  
Immune Cell Recruitment

Dendritic cells (DC) connect the innate and adaptive arms of the immune system and carry out numerous roles that are significant in the context of viral disease. Their functions include the control of inflammatory responses, the promotion of tolerance, cross-presentation, immune cell recruitment and the production of antiviral cytokines. Based primarily on the available literature that characterizes the behaviour of many DC subsets during Severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19), we speculated possible mechanisms through which DC could contribute to COVID-19 immune responses, such as dissemination of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to lymph nodes, mounting dysfunctional inteferon responses and T cell immunity in patients. We highlighted gaps of knowledge in our understanding of DC in COVID-19 pathogenesis and discussed current pre-clinical development of therapies for COVID-19.

Abstract TP224: Interleukin-37 Level is Elevated in Acute Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Saif Bushnaq ◽  
Atif Zafar ◽  
Kempuraj Duraisamy ◽  
Nudrat Tasneem ◽  
Mohammad M Khan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Inflammatory Responses ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Delayed Presentation ◽  
Stroke Patients ◽  
Post Stroke ◽  
Urine And Serum ◽  
Serum And Urine

Background: Interleukin-37 (IL-37) is a new member of IL-1 cytokine family with a defined role as a negative feedback inhibitor of pro-inflammatory responses. IL-37 has yet to be evaluated in non-immune neurological diseases like ischemic or hemorrhagic stroke. This study aimed to measure the urine and serum IL-37 levels in patients with acute ischemic stroke. Method: Twelve patients consented for the study. Two sets of serum and urine samples were obtained and analyzed; one upon admission to the hospital, and the second the next morning after overnight fasting. The trends in serum level of IL-37 in 5 stroke patients, while trends in urine level of 6 patients were available, measured by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Prior studies with healthy volunteers as control group have consistently showed IL-37 plasma level around or less than 65 pg/ml with maximum normal levels on ELISA approximated at 130 pg/ml. Results: IL-37 level in urine in stroke patients ranged from 297 - 4467. IL-37 levels were in the range of 300s to 1000s in patients with ischemic stroke compared with reported healthy controls in literature where the level was always less than 90. Three of these 10 patients presented within 3 hours of stroke onset with IL-37 serum levels being 2655 pg/ml, 3517 pg/ml and 5235 pg/ml. In all others, it ranged much less than that, with the trend of delayed presentation giving less IL-37 levels, both in urine and serum. There were no clear differences found in patients with or without tPA, diabetes, hyperlipidemia and high blood pressure in our small study. Conclusion: The study shows a rather stable elevation of IL-37 levels post-ischemic stroke, which if compared to available data from other studies, is 3-10 times elevated after acute ischemic stroke with an uptrend in the first few days. IL-37 plays some role in mediating post-stroke inflammation with significant rise in serum and urine IL-37 levels suggesting a key role of this novel cytokine in post-stroke pathology. This is the first ever reported study measuring and trending IL-37 levels in human plasma after an acute ischemic stroke.

scholarly journals Succinate Is an Inflammation-Induced Immunoregulatory Metabolite in Macrophages

Metabolites ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 372 ◽  
Author(s):  
Karl J. Harber ◽  
Kyra E. de Goede ◽  
Sanne G. S. Verberk ◽  
Elisa Meinster ◽  
Helga E. de Vries ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Cells ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cell Phenotype ◽  
Independent Manner ◽  
Inflammatory Macrophages ◽  
Necrosis Factor

Immunometabolism revealed the crucial role of cellular metabolism in controlling immune cell phenotype and functions. Macrophages, key immune cells that support progression of numerous inflammatory diseases, have been well described as undergoing vast metabolic rewiring upon activation. The immunometabolite succinate particularly gained a lot of attention and emerged as a crucial regulator of macrophage responses and inflammation. Succinate was originally described as a metabolite that supports inflammation via distinct routes. Recently, studies have indicated that succinate and its receptor SUCNR1 can suppress immune responses as well. These apparent contradictory effects might be due to specific experimental settings and particularly the use of distinct succinate forms. We therefore compared the phenotypic and functional effects of distinct succinate forms and receptor mouse models that were previously used for studying succinate immunomodulation. Here, we show that succinate can suppress secretion of inflammatory mediators IL-6, tumor necrosis factor (TNF) and nitric oxide (NO), as well as inhibit Il1b mRNA expression of inflammatory macrophages in a SUCNR1-independent manner. We also observed that macrophage SUCNR1 deficiency led to an enhanced inflammatory response without addition of exogenous succinate. While our study does not reveal new mechanistic insights into how succinate elicits different inflammatory responses, it does indicate that the inflammatory effects of succinate and its receptor SUCNR1 in macrophages are clearly context dependent.

scholarly journals Infarct Volume is a Major Determiner of Post-Stroke Immune Cell Function and Susceptibility to Infection

Stroke ◽  
2009 ◽  
Vol 40 (10) ◽  
pp. 3226-3232 ◽  
Author(s):  
Andreas Hug ◽  
Alexander Dalpke ◽  
Nina Wieczorek ◽  
Thomas Giese ◽  
Alexander Lorenz ◽  
...  
Keyword(s):  
Cell Function ◽  
Immune Cell ◽  
Infarct Volume ◽  
Immune Cell Function ◽  
Post Stroke ◽  
Susceptibility To Infection

Abstract TMP41: High-sensitivity C-Reactive Protein and Depression in Patients With Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Irene Katzan ◽  
Nicolas Thompson ◽  
Ahmed Itrat
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Responses ◽  
Fold Increase ◽  
Time Interval ◽  
Hscrp Level ◽  
Treatment Interventions ◽  
Post Stroke ◽  
Post Stroke Depression ◽  
New Treatment ◽  
Statin Use

Background: Depression is common in patients after stroke and is associated with worse outcomes Recognition of the causal factors contributing to post-stroke depression may lead to new treatment interventions. Ischemic stroke produces inflammatory responses and there is data to suggest that inflammation may promote depression. The objective of this analysis is to determine the association of hsCRP levels with depression in patients with ischemic stroke. Methods: We performed a retrospective cohort study of patients with ischemic stroke seen in a cerebrovascular clinic who completed a PHQ-9 depression screen and had a hsCRP level drawn between 28 days before or within 7 days after the PHQ-9 screen. Multivariate linear regression was performed:- the dependent variable was PHQ-9 score, the independent variable was log-transformed hsCRP. Additional covariates included age, sex, race (White vs. Black/Other), time since stroke (≤ 3 months vs. > 3 months), mRS score (0-2 vs. 3-5) and statin use at time of hsCRP draw (yes vs. no). Results: Between Feb 3, 2009 and March 14, 2014, 803 patients were seen in the cerebrovascular clinic with a diagnosis of ischemic stroke who had hscrp level. Of these, 220 patients had a hSCRP drawn within the prespecified time interval from PHQ9 screen. Mean age was 60.7 years, 43.2% were female and 78.6% were White. There was a significant independent association between hsCRP value and PHQ-9 score; For each 5-fold increase in hsCRP, the average PHQ-9 score increased by 1.22 points (95% CI 0.38 - 2.06, P = 0.005). Other variables independently associated with PHQ-9 score were: mRS > 2 (OR = 3.39, 95% CI 1.40 - 5.38), female (OR=-1.72 95% CI -3.11 - -0.32), and statin use (OR=-1.91, 95% CI -3.34 - -0.47). Conclusions: hsCRP level was independently associated with depressive symptoms. Understanding the association between inflammatory markers and depression following ischemic stroke may lead to the development of improved methods to predict post-stroke depression and new treatment interventions

scholarly journals Galectin-1 as an Emerging Mediator of Cardiovascular Inflammation: Mechanisms and Therapeutic Opportunities

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Ignacio M. Seropian ◽  
Germán E. González ◽  
Sebastián M. Maller ◽  
Daniel H. Berrocal ◽  
Antonio Abbate ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Ischemic Stroke ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Growth Factor Receptor ◽  
Treg Cells ◽  
Chagas Cardiomyopathy ◽  
Antigen Presenting ◽  
Endothelial Growth Factor

Galectin-1 (Gal-1), an evolutionarily conserved β-galactoside-binding lectin, controls immune cell homeostasis and tempers acute and chronic inflammation by blunting proinflammatory cytokine synthesis, engaging T-cell apoptotic programs, promoting expansion of T regulatory (Treg) cells, and deactivating antigen-presenting cells. In addition, this lectin promotes angiogenesis by co-opting the vascular endothelial growth factor receptor (VEGFR) 2 signaling pathway. Since a coordinated network of immunomodulatory and proangiogenic mediators controls cardiac homeostasis, this lectin has been proposed to play a key hierarchical role in cardiac pathophysiology via glycan-dependent regulation of inflammatory responses. Here, we discuss the emerging roles of Gal-1 in cardiovascular diseases including acute myocardial infarction, heart failure, Chagas cardiomyopathy, pulmonary hypertension, and ischemic stroke, highlighting underlying anti-inflammatory mechanisms and therapeutic opportunities. Whereas Gal-1 administration emerges as a potential novel treatment option in acute myocardial infarction and ischemic stroke, Gal-1 blockade may contribute to attenuate pulmonary arterial hypertension.

scholarly journals Lipid Nanoparticle Acts as a Potential Adjuvant for Influenza Split Vaccine without Inducing Inflammatory Responses

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 433
Author(s):  
Seiki Shirai ◽  
Atsushi Kawai ◽  
Meito Shibuya ◽  
Lisa Munakata ◽  
Daiki Omata ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cytokine Production ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Influenza Viruses ◽  
Inflammatory Cytokine Production ◽  
Virus Challenge ◽  
Aluminum Salts ◽  
Lipid Nanoparticle

Vaccination is a critical and reliable strategy for controlling the spread of influenza viruses in populations. Conventional seasonal split vaccines (SVs) for influenza evoke weaker immune responses than other types of vaccines, such as inactivated whole-virion vaccines, although SVs are highly safe compared to other types. Here, we assessed the potential of the lipid nanoparticle (LNP) we developed as an adjuvant for conventional influenza SV as an antigen in mice. The LNP did not induce the production of cytokines such as interleukin-6 (IL-6) and IL-12 p40 by dendritic cells or the expression of co-stimulatory molecules on these cells in vitro. In contrast, an SV adjuvanted with LNP improved SV-specific IgG1 and IgG2 responses and the Th1 response compared to the SV alone in mice. In addition, SV adjuvanted with an LNP gave superior protection against the influenza virus challenge over the SV alone and was as effective as SV adjuvanted with aluminum salts in mice. The LNP did not provoke inflammatory responses such as inflammatory cytokine production and inflammatory immune cell infiltration in mice, whereas aluminum salts induced inflammatory responses. These results suggest the potential of the LNP as an adjuvant without inflammatory responses for influenza SVs. Our strategy should be useful for developing influenza vaccines with enhanced efficacy and safety.

scholarly journals PD-L1 correlates with chemokines and cytokines in gingival crevicular fluid from healthy and diseased sites in subjects with periodontitis

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Andrew Shelby ◽  
Chandler Pendleton ◽  
Emma Thayer ◽  
Georgia K. Johnson ◽  
Xian Jin Xie ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Cell ◽  
Gingival Crevicular Fluid ◽  
Inflammatory Responses ◽  
Cell Trafficking ◽  
Periodontal Tissues ◽  
Cytokine Responses ◽  
Canonical Pathways ◽  
Checkpoint Molecule ◽  
Crevicular Fluid

Abstract Objective PD-L1 is an immune checkpoint molecule that regulates immune and inflammatory responses. While cells of periodontal tissues express PD-L1, its presence in GCF is not known. The purpose of this study was to measure the PD-L1 values in GCF and correlate values with the presence of chemokine and cytokine values from periodontally diseased subjects and periodontally healthy subjects. Results PD-L1 values (pg/30 s), determined in triplicate using a fluorescent microparticle-based immunoassay ranged from 0.04–31.65 pg/30 s. PD-L1 correlated with 15 out of 22 chemokine and cytokine responses. In 85 healthy sites in 31 subjects, PD-L1 values were negatively correlated with IL6, CXCL8, IL10, and CCL3 values. In 53 diseased sites in 20 subjects, PD-L1 values were positively correlated with CCL11, CSF2, IFNG, IL1A, IL1B, IL2, IL7, IL15, and CCL5 values and negatively correlated with IL12A and IL5 values. Gene ontology (GO) annotations identified roles of PD-L1 in Th1 and Th2 activation and T-cell exhaustion signaling canonical pathways. PD-L1 values were correlated with the expression of chemokines and cytokines, which likely regulates immune cell trafficking and protects the periodontium from uncontrolled immune responses to pathogens and inflammation-induced tissue damage.

scholarly journals MEKANISME IMUNODEPRESI PASCASTROKE

2019 ◽  
Vol 36 (3) ◽  
Author(s):  
Al Rasyid
Keyword(s):  
Immune Response ◽  
Nervous System ◽  
Ischemic Stroke ◽  
Immune System ◽  
Immune Responses ◽  
Functional Outcome ◽  
Hpa Axis ◽  
Post Stroke ◽  
Cholinergic Pathway

  POST-STROKE IMMUNODEPRESSION MECHANISMSABSTRACTImmunodepression refers to a condition when immune system has reduced capacity to fulfill its functions therefore leading to infection. Infections develop frequently after stroke, and have been associated with poor clinical and functional outcome. Several studies show ischemic stroke, leads to impairment of immune responses, which increases susceptibility of an infection. This review analyzes the mechanisms of post-stroke immunodepression involving nervous system, such as adrenergic pathway, cholinergic pathway, or HPA axis, comprehensively based on recent clinical and experimental evidences. A better understanding of immune system modification after stroke could encourage further studies regarding immunomodulation therapy use in fighting infection.Keywords: Immune response, infection, post-stroke immunodepressionABSTRAKImunodepresi merupakan suatu kondisi saat sistem imun tidak dapat menjalankan perannya dengan baik sehingga dapat menimbulkan suatu infeksi. Infeksi sendiri merupakan komplikasi yang umum terjadi pascastroke, dihubungkan dengan luaran klinis dan fungsional yang buruk pada pasien stroke. Berbagai studi klinis menyimpulkan kondisi iskemik pada stroke menyebabkan gangguan pada respons imun sehingga menimbulkan kerentanan terhadap infeksi. Tulisan ini membahas mekanisme imunodepresi pascastroke terkait sistem saraf, baik jalur adrenergik, kolinergik, dan aksis HPA, secara komprehensif berbasis bukti klinis maupun eksperimental. Pemahaman konsep modifikasi sistem imun pascastroke dapat mendorong studi-studi lanjutan terkait penggunaan terapi imunomodulasi untuk melawan komplikasi infeksi.Kata kunci: Imunodepresi pascastroke, infeksi, respons imun

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