scholarly journals Sustained Increases in Immune Transcripts and Immune Cell Trafficking During the Recovery of Experimental Brain Ischemia

Stroke ◽  
2020 ◽  
Vol 51 (8) ◽  
pp. 2514-2525 ◽  
Author(s):  
Wen Fury ◽  
Keun Woo Park ◽  
Zhuhao Wu ◽  
Eunhee Kim ◽  
Moon-sook Woo ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Immune Cells ◽  
Fluorescent Protein ◽  
Immune Cell ◽  
Chronic Phase ◽  
Mononuclear Phagocytes ◽  
Multiple Time ◽  
Immune Gene ◽  
Cell Trafficking ◽  
Time Points

Background and Purpose: Stroke is a major cause of chronic neurological disability. There is considerable interest in understanding how acute transcriptome changes evolve into subacute and chronic patterns that facilitate or limit spontaneous recovery. Here we mapped longitudinal changes in gene expression at multiple time points after stroke in mice out to 6 months. Methods: Adult C57BL/6 mice were subjected to transient middle cerebral artery occlusion. Longitudinal transcriptome levels were measured at 10 time points after stroke from acute to recovery phases of ischemic stroke. Localization and the number of mononuclear phagocytes were determined in the postischemic brain. Whole-mount brain imaging was performed in asplenic mice receiving GFP + (green fluorescent protein)-tagged splenocytes. Results: Sustained stroke-induced mRNA abundance changes were observed in both hemispheres with 2989 ipsilateral and 822 contralateral genes significantly perturbed. In the hemisphere ipsilateral to the infarct, genes associated with immune functions were strongly affected, including temporally overlapping innate and adaptive immunity and macrophage M1 and M2 phenotype-related genes. The strong immune gene activation was accompanied by the sustained infiltration of peripheral immune cells at acute, subacute, and recovery stages of stroke. The infiltrated immune cells were found in the infarcted area but also in remote regions at 2 months after stroke. Conclusions: The study identifies that immune components are the predominant molecular signatures and they may propagate or continuously respond to brain injury in the subacute to chronic phase after central nervous system injury. The study suggests a potential immune-based strategy to modify injury progression and tissue remodeling in ischemic stroke, even months after the initiating event.

Abstract 2874: Functional Polymorphisms in Toll-like Receptor 4 Predict Worse Outcome in Acute Ischemic Stroke Patients

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Jonathan R Weinstein ◽  
Juliane Schulze ◽  
Richard V Lee ◽  
Dannielle Zierath ◽  
Patricia Tanzi ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Immune Cell ◽  
Stroke Severity ◽  
Multiple Time ◽  
Toll Like Receptor ◽  
C Reactive Protein ◽  
Toll Like Receptor 4 ◽  
Reactive Protein ◽  
Functional Polymorphisms

Background: Toll-like receptor-4 (TLR4) plays a central role in the pathophysiology of acute ischemic stroke (AIS). Specific single nucleotide polymorphisms (SNPs) in TLR4 including 1063 A/G [Asp299Gly] and 1363 C/T [Thr399Ile] alter immune cell responsiveness to lipopolysaccharide (LPS) and are associated with increased rates of infection. The effect of these TLR4 SNPs on outcome following AIS is unknown. Methods: Patients were prospectively enrolled after onset of AIS. Clinical and demographic data were collected and neurological outcomes assessed at 3 months. Blood was drawn at multiple time points to quantify leukocyte subsets and assess plasma levels of C-reactive protein and a panel of cytokines. Genotyping for the TLR4 SNPs was also performed on blood samples. Uni- and multivariate analyses were performed to assess associations between TLR4 SNP haplotype and (i) each laboratory parameter noted above, (ii) infection risk and (iii) stroke outcome. Results: Of the 42 patients included; 6 (14%) were heterozygous for either one or both TLR4 SNPs. Baseline characteristics were similar in patients with or without a TLR4 SNP. In analyses adjusted for both initial stroke severity and age, the presence of a TLR4 SNP was associated with increases in blood leukocytes, plasma C-reactive protein and the cytokine interleukin-1 receptor antagonist (IL-1ra). The presence of either TLR4 SNP was also associated with a trend toward increased rates of infection (adjusted odds ratio and 95% confidence interval of 8.20 and 0.826-81.5, respectively) and a decreased likelihood of favorable outcome as defined by a modified Rankin Scale score of two or less at three months from stroke onset (0.014, 0.00-0.759). Conclusions: In AIS patients, functionally significant genetic variations in TLR4 influence both rates of stroke-associated infection and neurological outcome. These data suggest a direct connection between TLR4 function and stroke pathophysiology.

scholarly journals Myeloid Immune Cells CARriying a New Weapon Against Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Rodrigo Nalio Ramos ◽  
Samuel Campanelli Freitas Couto ◽  
Theo Gremen M. Oliveira ◽  
Paulo Klinger ◽  
Tarcio Teodoro Braga ◽  
...  
Keyword(s):  
Gene Therapy ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Solid Tumors ◽  
Immune Cells ◽  
Scientific Community ◽  
Immune Cell ◽  
Clinical Results ◽  
Mononuclear Phagocytes ◽  
Soluble Factors

Chimeric antigen receptor (CAR) engineering for T cells and natural killer cells (NK) are now under clinical evaluation for the treatment of hematologic cancers. Although encouraging clinical results have been reported for hematologic diseases, pre-clinical studies in solid tumors have failed to prove the same effectiveness. Thus, there is a growing interest of the scientific community to find other immune cell candidate to express CAR for the treatment of solid tumors and other diseases. Mononuclear phagocytes may be the most adapted group of cells with potential to overcome the dense barrier imposed by solid tumors. In addition, intrinsic features of these cells, such as migration, phagocytic capability, release of soluble factors and adaptive immunity activation, could be further explored along with gene therapy approaches. Here, we discuss the elements that constitute the tumor microenvironment, the features and advantages of these cell subtypes and the latest studies using CAR-myeloid immune cells in solid tumor models.

scholarly journals Exosomal delivery of NF-κB inhibitor delays LPS-induced preterm birth and modulates fetal immune cell profile in mouse models

2021 ◽  
Vol 7 (4) ◽  
pp. eabd3865
Author(s):  
Samantha Sheller-Miller ◽  
Enkhtuya Radnaa ◽  
Jae-Kwang Yoo ◽  
Eunsoo Kim ◽  
Kyungsun Choi ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Inflammatory Response ◽  
Immune Cells ◽  
Fluorescent Protein ◽  
Immune Cell ◽  
Innate Immune ◽  
Maternal Inflammation ◽  
Lps Challenge ◽  
Cell Profile ◽  
Fetal Inflammatory Response

Accumulation of immune cells and activation of the pro-inflammatory transcription factor NF-κB in feto-maternal uterine tissues is a key feature of preterm birth (PTB) pathophysiology. Reduction of the fetal inflammatory response and NF-κB activation are key strategies to minimize infection-associated PTB. Therefore, we engineered extracellular vesicles (exosomes) to contain an NF-κB inhibitor, termed super-repressor (SR) IκBα. Treatment with SR exosomes (1 × 1010 per intraperitoneal injection) after lipopolysaccharide (LPS) challenge on gestation day 15 (E15) prolonged gestation by over 24 hours (PTB ≤ E18.5) and reduced maternal inflammation (n ≥ 4). Furthermore, using a transgenic model in which fetal tissues express the red fluorescent protein tdTomato while maternal tissues do not, we report that LPS-induced PTB in mice is associated with influx of fetal innate immune cells, not maternal, into feto-maternal uterine tissues. SR packaged in exosomes provides a stable and specific intervention for reducing the inflammatory response associated with PTB.

scholarly journals Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy

2021 ◽  
Vol 22 (18) ◽  
pp. 9804
Author(s):  
Pedro Bule ◽  
Sandra I. Aguiar ◽  
Frederico Aires-Da-Silva ◽  
Joana N. R. Dias
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Cell ◽  
Vascular Endothelial Cells ◽  
Tumor Biology ◽  
Large Family ◽  
Response To Therapy ◽  
Cell Trafficking ◽  
Immunotherapy Target ◽  
Patient Prognosis

Chemokines are a large family of small chemotactic cytokines that coordinates immune cell trafficking. In cancer, they have a pivotal role in the migration pattern of immune cells into the tumor, thereby shaping the tumor microenvironment immune profile, often towards a pro-tumorigenic state. Furthermore, chemokines can directly target non-immune cells in the tumor microenvironment, including cancer, stromal and vascular endothelial cells. As such, chemokines participate in several cancer development processes such as angiogenesis, metastasis, cancer cell proliferation, stemness and invasiveness, and are therefore key determinants of disease progression, with a strong influence in patient prognosis and response to therapy. Due to their multifaceted role in the tumor immune response and tumor biology, the chemokine network has emerged as a potential immunotherapy target. Under the present review, we provide a general overview of chemokine effects on several tumoral processes, as well as a description of the currently available chemokine-directed therapies, highlighting their potential both as monotherapy or in combination with standard chemotherapy or other immunotherapies. Finally, we discuss the most critical challenges and prospects of developing targeted chemokines as therapeutic options.

scholarly journals Multiplexed, sequential secretion analysis of the same single cells reveals distinct effector response dynamics dependent on the initial basal state

2019 ◽  
Author(s):  
Zhuo Chen ◽  
Yao Lu ◽  
Kerou Zhang ◽  
Yang Xiao ◽  
Jun Lu ◽  
...  
Keyword(s):  
Immune Cells ◽  
Time Course ◽  
Single Cells ◽  
Human Macrophage ◽  
Transcriptional Level ◽  
Multiple Time ◽  
Response Dynamics ◽  
Macrophage Response ◽  
Time Points ◽  
Effector Response

AbstractThe effector response of immune cells dictated by an array of secreted proteins is a highly dynamic process, requiring sequential measurement of all relevant proteins from single cells. Herein we show a microchip-based, 10-plexed, sequential secretion assay on the same single cells and at the scale of ~5000 single cells measured simultaneously over 4 time points. It was applied to investigating the time course of single human macrophage response to Toll-like receptor 4 (TLR4) ligand lipopolysaccharide and revealed four distinct activation modes for different proteins in single cells. In particular, we observed that secreted factors regulated by transcription factor NFkB (e.g., TNF and CCL2) predominantly show on-off mode over off-on mode. The dynamics of all proteins combined classified the cells into two major activation states, which were found to be dependent on the basal state of each cell. Single-cell RNA-Seq was performed on the same samples at the matched time points and further demonstrated at the transcriptional level the existence of two major activation states, which are enriched for translation vs inflammatory programs, respectively. These results showed a cell-intrinsic heterogeneous response in phenotypically homogeneous cell population. This work demonstrated the longitudinal tracking of protein secretion signature in thousands of single cells at multiple time points, providing dynamic information to better understand how individual immune cells react to pathogenic challenges over time and how they together constitute a population response.

scholarly journals Five Genes as Diagnostic Markers of Ischemic Stroke and Their Correlation with Immune Infiltration

2021 ◽  
Author(s):  
Meng Wang ◽  
Ruijie Zhang ◽  
Qiongfeng Guan ◽  
Yindan Yao ◽  
Liyuan Han
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Ischemic Stroke ◽  
Immune Cells ◽  
Immune Cell ◽  
Diagnostic Markers ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Γδt Cells ◽  
Negatively Associated

Abstract Background: This study aimed to identify potential diagnostic markers of ischemic stroke (IS) and discuss the function of immune cell infiltration during the pathological process. Methods: We used IS datasets from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified, and functional correlation analysis was performed. We then screened and verified the diagnostic markers of IS. We evaluated the infiltration of immune cells in infarcts using CIBERSORT and analyzed the correlation between diagnostic markers and infiltrating immune cells. Results: A total of 366 DEGs were screened in this study. Genes encoding CTSG, F13A1, PABPC1, ECHDC2, BIRC2 and infiltrating monocytes, M0 macrophages, activated dendritic cells, and neutrophils (area under the curve [AUC] = 0.945) were identified as diagnostic markers of IS. Immune cell infiltration analysis suggested that memory B cells, regulatory T cells, M0 macrophages, CD8 + T cells, γδT cells, activated natural killer cells, monocytes, activated mast cells, and neutrophils were involved in the IS process. Analysis of correlations between expressed genes and infiltrating immune cells found that CTSG was positively associated with M0 macrophages, F13A1 was positively associated with monocytes, PABPC1 was positively associated with activated dendritic cells, eosinophils were negatively associated with neutrophils, ECHDC2 was negatively associated with monocytes, and BIRC2 was positively associated with eosinophils. Conclusion: five genes and four types of immune cells were identified as diagnostic markers of IS, and immune cell infiltration may play an important role in the progression of IS.

scholarly journals Systematic Study of the Immune Components after Ischemic Stroke Using CyTOF Techniques

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Yaning Li ◽  
Yan Wang ◽  
Yang Yao ◽  
Brian B. Griffiths ◽  
Liangshu Feng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Immune Cells ◽  
Immune Cell ◽  
Deep Understanding ◽  
Cell Types ◽  
Lymphoid Tissues ◽  
Peripheral Tissues ◽  
Ischemic Brain ◽  
Peripheral Organs ◽  
The Brain

Stroke induces a robust inflammatory response. However, it still lacks a systematic view of the various immune cell types due to the limited numbers of fluorophore used in the traditional FACS technique. In our current study, we utilized the novel technique mass cytometry (CyTOF) to analyze multiple immune cell types. We detected these immune cells from the ischemic brain, peripheral blood, spleen, and bone marrow at different time courses after stroke. Our data showed (1) dynamic changes in the immune cell numbers in the ischemic brain and peripheral organs. (2) The expression levels of cell surface markers indicate the inflammation response status after stroke. Interestingly, CD62L, a key adhesion molecule, regulates the migration of leukocytes from blood vessels into secondary lymphoid tissues and peripheral tissues. (3) A strong leukocyte network across the brain and peripheral immune organs was identified using the R program at day 1 after ischemia, suggesting that the peripheral immune cells dramatically migrated into the ischemic areas after stroke. This study provides a systematic, wide view of the immune components in the brain and peripheral organs for a deep understanding of the immune response after ischemic stroke.

scholarly journals A Dynamic in vitro BBB Model for the Study of Immune Cell Trafficking into the Central Nervous System

2010 ◽  
Vol 31 (2) ◽  
pp. 767-777 ◽  
Author(s):  
Luca Cucullo ◽  
Nicola Marchi ◽  
Mohammed Hossain ◽  
Damir Janigro
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Cell Trafficking ◽  
In Vitro System ◽  
Immune Cell Trafficking ◽  
The Central Nervous System ◽  
In Vitro Bbb Model ◽  
The Brain

Although there is significant evidence correlating overreacting or perhaps misguided immune cells and the blood–brain barrier (BBB) with the pathogenesis of neuroinflammatory diseases, the mechanisms by which they enter the brain are largely unknown. For this purpose, we revised our humanized dynamic in vitro BBB model (DIV-BBBr) to incorporate modified hollow fibers that now feature transmural microholes (2 to 4 μm Ø) allowing for the transendothelial trafficking of immune cells. As with the original model, this new DIV-BBBr reproduces most of the physiological characteristics of the BBB in vivo. Measurements of transendothelial electrical resistance (TEER), sucrose permeability, and BBB integrity during reversible osmotic disruption with mannitol (1.6 mol/L) showed that the microholes do not hamper the formation of a tight functional barrier. The in vivo rank permeability order of sucrose, phenytoin, and diazepam was successfully reproduced in vitro. Flow cessation followed by reperfusion (Fc/Rp) in the presence of circulating monocytes caused a biphasic BBB opening paralleled by a significant increase of proinflammatory cytokines and activated matrix metalloproteinases. We also observed abluminal extravasation of monocytes but only when the BBB was breached. In conclusion, the DIV-BBBr represents the most realistic in vitro system to study the immune cell trafficking across the BBB.

scholarly journals Choroid Plexus-Selective Inactivation of Adenosine A2A Receptors Protects Against T Cell Infiltration And Experimental Autoimmune Encephalomyelitis

2021 ◽  
Author(s):  
Wu Zheng ◽  
Yijia Feng ◽  
Zhenhai Zeng ◽  
Mengqian Ye ◽  
Huiping Shang ◽  
...  
Keyword(s):  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Cell Trafficking ◽  
Autoimmune Encephalomyelitis ◽  
Post Immunization ◽  
T Cell Infiltration ◽  
Experimental Autoimmune

Abstract Background: Multiple sclerosis (MS) is one of the most common autoimmune disorders characterized by the infiltration of immune cells into the brain and demyelination. The unwanted immunosuppressive side effect of therapeutically successful natalizumab led us to focus on choroid plexus (CP), a key site for the first wave of immune cell infiltration in experimental autoimmune encephalomyelitis (EAE), for the control of immune cells trafficking. Adenosine A2A receptor (A2AR) is emerging as a potential pharmacological target to control EAE pathogenesis; however, the cellular basis for the A2AR-mediated protection remains undetermined. Methods: In EAE model, we assessed A2AR expression and leukocyte trafficking determinants in CP by immunohistochemistry and qPCR analyses. We determined the effect of the A2AR antagonist KW6002 treatment at days 8-12 or 8-14 post-immunization on T cell infiltration across CP and EAE pathology. We determined the critical role of the CP-A2AR on T cell infiltration and EAE pathology by focal knockdown the CP-A2AR with intracerebroventricular injection of CRE-TAT recombinase into the A2ARflox/flox mice. In cultured CP epithelium, we also evaluated the effect of overexpression of A2ARs or the A2AR agonist CGS21680 treatment on CP permeability and lymphocytes migration. Results: We found the specific upregulation of A2AR in CP in association with enhanced CP gateway activity peaked at day 12 post-immunization in EAE mice. Furthermore, the KW6002 treatment at days 8-12 or 8-14 post-immunization reduced T-cell trafficking across CP and attenuated EAE pathology. Importantly, focal CP-A2AR knockdown attenuated pathogenic infiltration of Th17+ cells across CP via inhibiting CCR6-CCL20 axis through NFκB / STAT3 pathway and protected against EAE pathology. Lastly, activation of A2AR in cultured epithelium by A2AR overexpression or CGS21680 treatment increased the permeability of CP epithelium and facilitated lymphocytes migration. Conclusion: These findings define the CP niche as one of the primary sites of A2AR action whereby A2AR antagonists confer protection against EAE pathology. Thus, pharmacological targeting of the CP-A2AR represents a novel therapeutic strategy for MS by controlling immune cell trafficking across CP.

scholarly journals Anti-Integrin Therapy for Multiple Sclerosis

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Eiji Kawamoto ◽  
Susumu Nakahashi ◽  
Takayuki Okamoto ◽  
Hiroshi Imai ◽  
Motomu Shimaoka
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Cell Adhesion ◽  
Immune Cells ◽  
Cell Adhesion Molecules ◽  
Immune Cell ◽  
Critical Role ◽  
Cell Trafficking ◽  
Organ Specific ◽  
Integrin Alpha4

Integrins are the foremost family of cell adhesion molecules that regulate immune cell trafficking in health and diseases. Integrin alpha4 mediates organ-specific migration of immune cells to the inflamed brain, thereby playing the critical role in the pathogenesis of multiple sclerosis. Anti-alpha4 integrin therapy aiming to block infiltration of autoreactive lymphocytes to the inflamed brain has been validated in several clinical trials for the treatment of multiple sclerosis. This paper provides readers with an overview of the molecular and structural bases of integrin activation as well as rationale for using anti-alpha4 integrin therapy for multiple sclerosis and then chronicles the rise and fall of this treatment strategy using natalizumab, a humanized anti-alpha4 integrin.

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