MicroRNAs in the regulation of immune cell functions – implications for atherosclerotic vascular disease

2012 ◽  
Vol 107 (04) ◽  
pp. 626-633 ◽  
Author(s):  
Alma Zernecke
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Chronic Inflammatory Disease ◽  
Vascular Pathology ◽  
Lipid Uptake ◽  
T Helper ◽  
Atherosclerotic Vascular Disease ◽  
Cell Functions

SummaryRegarded as a chronic inflammatory disease of the vessel wall, the development of atherosclerotic lesions is shaped by immune responses and their regulation. Macrophages and dendritic cells are positioned at the crossroad of innate and adaptive immune responses by sensing atherogenic danger signals and by taking up and presenting antigens. T helper cells and auto-antibodies produced by B cells, together with their cytokine responses in turn modulate atheroprogression. In addition, platelets contribute to atherosclerosis by multiple pathways. microRNAs (miRNAs) that post-transcriptionally regulate gene expression may thus critically control immune cell differentiation and functions during plaque evolution. This review summarises the role of miRNAs in regulating lipid uptake and expression of inflammatory mediators in monocytes/macrophages and dendritic cells, in lymphocyte functions with a focus on T helper cell responses, as well as in platelet biology, and the implications of altering these functions in vascular pathology and atherosclerosis. T systematically survey miRNA functions in controlling molecular mechanisms and immune responses in atherosclerosis holds potential for the development of novel miRNA-based strategies for therapies targeting inflammation and immunity in atherosclerosis.

scholarly journals Selenium, Selenoproteins, and Immunity

Nutrients ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 1203 ◽  
Author(s):  
Joseph Avery ◽  
Peter Hoffmann
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
High Throughput ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Biological Effects ◽  
Cell Functions ◽  
Experimental Systems ◽  
Physiological Processes

Selenium is an essential micronutrient that plays a crucial role in development and a wide variety of physiological processes including effect immune responses. The immune system relies on adequate dietary selenium intake and this nutrient exerts its biological effects mostly through its incorporation into selenoproteins. The selenoproteome contains 25 members in humans that exhibit a wide variety of functions. The development of high-throughput omic approaches and novel bioinformatics tools has led to new insights regarding the effects of selenium and selenoproteins in human immuno-biology. Equally important are the innovative experimental systems that have emerged to interrogate molecular mechanisms underlying those effects. This review presents a summary of the current understanding of the role of selenium and selenoproteins in regulating immune cell functions and how dysregulation of these processes may lead to inflammation or immune-related diseases.

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.

scholarly journals 641 Spatially organized multicellular immune hubs in MMRd and MMRp colorectal cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A670-A670
Author(s):  
Jonathan Chen ◽  
Karin Pelka ◽  
Matan Hofree ◽  
Marios Giannakis ◽  
Genevieve Boland ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Mismatch Repair ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Single Cells ◽  
Large Set ◽  
Colon Tissue

BackgroundImmune responses to cancer are highly variable, with DNA mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. Almost all tumors are infiltrated with immune cells, but the types of immune responses and their effects on tumor growth, metastasis and death, vary greatly between different cancers and individual tumors. Which of the numerous cell subsets in a tumor contribute to the response, how their interactions are regulated, and how they are spatially organized within tumors remains poorly understood.MethodsTo understand the rules governing these varied responses, we transcriptionally profiled 371,223 single cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd treatment-naive patients. We developed a systematic approach to discover cell types, their underlying gene programs, and cellular communities based on single cell RNA-seq (scRNAseq) profiles and applied it to study the distinguishing features of human MMRd and MMRp colorectal cancer. Cellular communities discovered from this analysis were spatially mapped in tissue sections using multiplex RNA in situ hybridization microscopy.ResultsTo understand the basis for differential immune responses in CRC, we first determined and compared the immune cell composition of MMRd and MMRp CRC and normal colon tissue, finding dramatic remodeling between tumor and normal tissue and between MMRd and MMRp tumors, particularly within the myeloid, T cell, and stromal compartments. Among the clusters enriched in MMRd tumors were activated CXCL13+ CD8 T cells. Importantly, gene program co-variation analysis revealed multicellular networks. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage, and an MMRd-enriched immune hub within the tumor, with activated IFNG+ and CXCL13+ T cells together with malignant and myeloid cells expressing T-cell-attracting chemokines (figure 1).ConclusionsOur study provides a rich dataset of cellular states, gene programs and their transformations in tumors across a relatively large cohort of patients with colorectal cancer. Our predictions of several multicellular hubs based on co-variation of gene expression programs, and subsequent spatial localization of two major immune-malignant hubs, organizes a large set of cell states and programs into a smaller number of coordinated networks of cells and processes. Understanding the molecular mechanisms underlying these hubs, and studying their temporal and spatial regulation upon treatment will be critical for advancing cancer therapy.Ethics ApprovalThis study was approved by the DF-HCC institutional review board (protocols 03-189 and 02-240).Abstract 641 Figure 1A coordinated network of CXCL13+ T cells with myeloid and malignant cells expressing ISGs. Image shows a portion of formalin-fixed paraffin-embedded tissue from an MMRd CRC specimen stained with multiplex RNA ISH / IF for PanCK-IF, CD3E-ISH, CXCL10/CXCL11-ISH, CXCL13-ISH, and IFNG-ISH. Note IFNG+ and CXCL13+ cells in proximity to cells expressing the chemokines CXCL10/CXCL11

scholarly journals Toll-Like Receptor-4 Is Involved in Mediating Intestinal and Extra-Intestinal Inflammation in Campylobacter coli-Infected Secondary Abiotic IL-10−/− Mice

2020 ◽  
Vol 8 (12) ◽  
pp. 1882
Author(s):  
Sigri Kløve ◽  
Claudia Genger ◽  
Dennis Weschka ◽  
Soraya Mousavi ◽  
Stefan Bereswill ◽  
...  
Keyword(s):  
Immune Responses ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Clinical Signs ◽  
Campylobacter Coli ◽  
Toll Like Receptor ◽  
Host Interactions ◽  
Non Invasive ◽  
Health Burdens

Human Campylobacter infections are emerging worldwide and constitute significant health burdens. We recently showed that the immunopathological sequelae in Campylobacter jejuni-infected mice were due to Toll-like receptor (TLR)-4 dependent immune responses induced by bacterial lipooligosaccharide (LOS). Information regarding the molecular mechanisms underlying Campylobacter coli-host interactions are scarce, however. Therefore, we analyzed C. coli-induced campylobacteriosis in secondary abiotic IL-10−/− mice with and without TLR4. Mice were infected perorally with a human C. coli isolate or with a murine commensal Escherichia coli as apathogenic, non-invasive control. Independent from TLR4, C. coli and E. coli stably colonized the gastrointestinal tract, but only C. coli induced clinical signs of campylobacteriosis. TLR4−/− IL-10−/− mice, however, displayed less frequently fecal blood and less distinct histopathological and apoptotic sequelae in the colon versus IL-10−/− counterparts on day 28 following C. coli infection. Furthermore, C. coli-induced colonic immune cell responses were less pronounced in TLR4−/− IL-10−/− as compared to IL-10−/− mice and accompanied by lower pro-inflammatory mediator concentrations in the intestines and the liver of the former versus the latter. In conclusion, our study provides evidence that TLR4 is involved in mediating C. coli-LOS-induced immune responses in intestinal and extra-intestinal compartments during murine campylobacteriosis.

scholarly journals Friend virus limits adaptive cellular immune responses by imprinting a maturation-resistant and T helper type 2-biased immunophenotype in dendritic cells

PLoS ONE ◽  
2018 ◽  
Vol 13 (2) ◽  
pp. e0192541 ◽  
Author(s):  
Limei Shen ◽  
Stefan Tenzer ◽  
Moritz Hess ◽  
Ute Distler ◽  
Ingrid Tubbe ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Friend Virus ◽  
T Helper ◽  
Cellular Immune Responses ◽  
Cellular Immune ◽  
Helper Type

The TLR7/8 Ligand R848 Is Superior In Generation of Monocyte Derived Dendritic Cells From AML Patients for the Induction of Potent T and NK Cell Immune Responses

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2195-2195
Author(s):  
Daniela Dorfel ◽  
Barbara Beck ◽  
Christiane Geiger ◽  
Felix Lichtenegger ◽  
Lysann Lindner ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Nk Cell ◽  
Residual Disease ◽  
Healthy Controls ◽  
T Helper ◽  
Tlr Agonists ◽  
Migratory Capacity ◽  
Healthy Donors ◽  
Minimal Residual

Abstract Abstract 2195 Introduction: Therapeutic vaccination with dendritic cells (DC) is currently considered as an investigational therapy in acute myeloid leukemia (AML) for eradication of minimal residual disease (MRD). Dendritic cells derived from autologous peripheral blood monocytes have been tested as cellular adjuvants for therapeutic vaccination of malignancies and proven feasibility and safety, but overall clinical response rates remain very low. The vast majority of DCs used for clinical trials were differentiated with a standard maturation cocktail composed of the cytokines TNF-a, IL-1b, IL-6 and PGE2 leading to DCs unable to secrete biologically active IL-12. This cytokine is fervently desired because of its leading role in promoting T helper 1 cell polarization and therefore fostering the appropriate adaptive immune responses needed to combat minimal residual disease. Cocktails containing synthetic Toll-like receptors (TLR) agonists emerged as an attractive alternative for the induction of DC maturation with T helper type 1 polarizing capacity. Our present investigation was designed to study the feasability of a clinical grade DC 3-day mDC generation protocol from nonleukemic monocytes of intensively pretreated AML patients with novel maturation cocktails containing different TLR-agonists in vitro and assessment of their potency to induce adaptive and innate immune responses. Material & Methods: Monocytes isolated from peripheral blood of AML patients in CR and healthy donors were differentiated into immature DC with GM-CSF and IL-4. After 48 hours DC were additionally cultured with TNF-a, IL1-b, INF-g, PGE2 and corresponding to the defined cocktail with the TLR7/8 agonists R848 (R) or CL075 (C) with or without the TLR3 agonist poly(I:C) (P) for 24 hours. mDCs were analyzed for expression of maturation surface markers, costimulatory profile, IL-12(p70)/IL-10 ratio, migratory capacity, NK cell activation and polarization of T cells. Results: No significant difference in absolute monocyte counts and percentage of DC recovery between healthy controls and AML patients in CR was found using different maturation cocktails (C, CP, R, and RP). Phenotype analysis of surface marker expression revealed no substantial differences between the different DC generation protocols used in healthy donors and AML patients in CR. The costimulatory profile assesed by the expression of two members of the B7 family, CD80 (B7.1) and CD274 (B7-H1 or PD-L1), was in healthy donors superior to AML patients, but these differences were not statistically significant. Variations were noted in the capacity of DCs derived from different donors to produce IL-12(p70) and IL-10, but importantly no significant differences between AML patients in CR and healthy controls could be observed. Interestingly, both healthy donor and AML derived DCs secrete a significantly higher proportion of IL-12(p70) with R848 containing cocktails compared to CL075. Treatment with the CP cocktails even leads to a inverse Il12/IL-10 ratio in AML patients. The high CCR7 expression was paralleled by a strong migratory capacity as well as positive chemotactic reponses to CCL19 chemokine signals. DCs matured with these novel cocktails induced potent alloresponses and strongly activated NK cells measured by upregulation of CD69 expression and IFN-g secretion. No differences beetween R848 and CL075 could be observed. Conclusion: Here we report for the first time a clinically applicable, time- and resource saving 3-day TLR-agonist containing maturation protocol for the generation of IL-12(p70) secreting DCs from AML patients in remission validated with healthy controls which allowed efficient generation, easy harvesting, stable maturation and substantial recoveries of mature DCs. Comparison of different TLR7/8 agonists showed superiority of R848 in IL-12(p70) production to CL075. We believe that these studies point the way to improved DCs that will induce better and long lasting immune responses in the vaccination against acute myelo Disclosures: No relevant conflicts of interest to declare.

scholarly journals CD4+ CD25+ Regulatory T Cells Control T Helper Cell Type 1 Responses to Foreign Antigens Induced by Mature Dendritic Cells In Vivo

2003 ◽  
Vol 198 (2) ◽  
pp. 259-266 ◽  
Author(s):  
Guillaume Oldenhove ◽  
Magali de Heusch ◽  
Georgette Urbain-Vansanten ◽  
Jacques Urbain ◽  
Charlie Maliszewski ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Peripheral Tolerance ◽  
T Helper Cell ◽  
Helper Cell ◽  
T Helper

Recent evidence suggests that in addition to their well known stimulatory properties, dendritic cells (DCs) may play a major role in peripheral tolerance. It is still unclear whether a distinct subtype or activation status of DC exists that promotes the differentiation of suppressor rather than effector T cells from naive precursors. In this work, we tested whether the naturally occurring CD4+ CD25+ regulatory T cells (Treg) may control immune responses induced by DCs in vivo. We characterized the immune response induced by adoptive transfer of antigen-pulsed mature DCs into mice depleted or not of CD25+ cells. We found that the development of major histocompatibility complex class I and II–restricted interferon γ–producing cells was consistently enhanced in the absence of Treg. By contrast, T helper cell (Th)2 priming was down-regulated in the same conditions. This regulation was independent of interleukin 10 production by DCs. Of note, splenic DCs incubated in vitro with Toll-like receptor ligands (lipopolysaccharide or CpG) activated immune responses that remained sensitive to Treg function. Our data further show that mature DCs induced higher cytotoxic activity in CD25-depleted recipients as compared with untreated hosts. We conclude that Treg naturally exert a negative feedback mechanism on Th1-type responses induced by mature DCs in vivo.

scholarly journals Targeting Mycobacterium tuberculosis Antigens to Dendritic Cells via the DC-Specific-ICAM3-Grabbing-Nonintegrin Receptor Induces Strong T-Helper 1 Immune Responses

2018 ◽  
Vol 9 ◽  
Author(s):  
Lis Noelia Velasquez ◽  
Philipp Stüve ◽  
Maria Virginia Gentilini ◽  
Maxine Swallow ◽  
Judith Bartel ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
T Helper ◽  
T Helper 1

scholarly journals Blood-derived inflammatory dendritic cells in lymph nodes stimulate acute T helper type 1 immune responses

2009 ◽  
Vol 10 (4) ◽  
pp. 394-402 ◽  
Author(s):  
Hideki Nakano ◽  
Kaifeng Lisa Lin ◽  
Manabu Yanagita ◽  
Chantal Charbonneau ◽  
Donald N Cook ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Lymph Nodes ◽  
T Helper ◽  
Inflammatory Dendritic Cells ◽  
Helper Type

scholarly journals Dendritic Cells under Hypoxia: How Oxygen Shortage Affects the Linkage between Innate and Adaptive Immunity

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Sandra Winning ◽  
Joachim Fandrey
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Mature Dendritic Cell ◽  
Innate And Adaptive Immunity ◽  
Cell Functions ◽  
Adaptive Immune ◽  
Oxygen Shortage

Dendritic cells (DCs) are considered as one of the main regulators of immune responses. They collect antigens, process them, and present typical antigenic structures to lymphocytes, thereby inducing an adaptive immune response. All these processes take place under conditions of oxygen shortage (hypoxia) which is often not considered in experimental settings. This review highlights how deeply hypoxia modulates human as well as mouse immature and mature dendritic cell functions. It tries to linkin vitroresults to actualin vivostudies and outlines how hypoxia-mediated shaping of dendritic cells affects the activation of (innate) immunity.

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