MicroRNA-155 expression suggests a sex disparity in innate lymphoid cells at the single-cell level.
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ABSTRACT:
SUBMITTER: Malmhall C
PROVIDER: S-EPMC7193614 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
Publications
MicroRNA-155 expression suggests a sex disparity in innate lymphoid cells at the single-cell level.
Malmhäll Carina C Weidner Julie J Rådinger Madeleine M
Cellular & molecular immunology 20191010 5
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Project description:Group-2 innate lymphoid cells (ILC2) play critical roles in the initiation and maintenance of type-2 immune responses, predominantly through their production of the type-2 cytokines IL-5, IL-9, and IL-13. ILC2 are essential for the efficient elimination of helminth parasites, but also contribute to the detrimental type-2 immune responses that underlie diseases such as asthma and allergy. While several transcription factors have been identified that regulate the development and function of ILC2, less is known about the post-transcriptional mechanisms that regulate these processes. We identified micro-RNAs (miRNAs) that are co-ordinately regulated in ILC2 from mice exposed to two different stimuli, namely IL-33 "alarmin" administration or Nippostrongylus brasiliensis parasitic worm infection. miR-155 is upregulated in ILC2 in response to both stimuli and miR-155-/- mice had impaired IL-33-driven ILC2 responses. Using mixed bone marrow chimeras, we demonstrate that this deficit is intrinsic to ILC2 and that miR-155 protects ILC2 from apoptosis, while having little impact on ILC2 proliferation or cytokine production. These data reveal a subset of miRNAs that are regulated upon ILC2 activation and establish a specific role for miR-155 in regulating ILC2 survival following activation.
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Project description:The transcriptomic signatures that shape responses of innate lymphoid cells (ILCs) have been well characterised, however post-transcriptional mechanisms which regulate their development and activity remain poorly understood. We demonstrate that ILC groups of the intestinal lamina propria express mature forms of microRNA-142 (miR-142), an evolutionarily conserved microRNA family with several non-redundant regulatory roles within the immune system. Germline Mir142 deletion alters intestinal ILC compositions, resulting in the absence of T-bet+ populations and significant defects in the cellularity and phenotypes of ILC3 subsets including CCR6+ LTi-like ILC3s. These effects were associated with decreased pathology in an innate-immune cell driven model of colitis. Furthermore, Mir142-/- mice demonstrate defective development of gut-associated lymphoid tissues, including a complete absence of mature Peyer's patches. Conditional deletion of Mir142 in ILC3s (RorcΔMir142) supported cell-intrinsic roles for these microRNAs in establishing or maintaining cellularity and functions of LTi-like ILC3s in intestinal associated tissues. RNAseq analysis revealed several target genes and biological pathways potentially regulated by miR-142 microRNAs in these cells. Finally, lack of Mir142 in ILC3 led to elevated IL-17A production. These data broaden our understanding of immune system roles of miR-142 microRNAs, identifying these molecules as critical post-transcriptional regulators of ILC3s and intestinal mucosal immunity.
| S-EPMC11835792 | biostudies-literature
Project description:Computational prediction of microRNA targets remains a challenging problem. The existing rule-based, data-driven and expression profiling approaches to target prediction are mostly approached from the gene-level. The increasing availability of RNA-seq data provides a new perspective for microRNA target prediction on the isoform-level. We hypothesize that the splicing isoform is the ultimate effector in microRNA targeting and that the proposed isoform-level approach is capable of predicting non-dominant isoform targets as well as their targeting regions that are otherwise invisible to many existing approaches. To test the hypothesis, we used an iterative expectation maximization (EM) algorithm to quantify transcriptomes at the isoform-level. The performance of the EM algorithm in transcriptome quantification was examined in simulation studies using FluxSimulator. We used joint evidence from isoform-level down-regulation and seed enrichment to predict microRNA-155 targets. We validated our computational approach using results from 149 in-house performed in vitro 3'-UTR assays. We also augmented the splicing database using exon-exon junction evidence, and applied the EM algorithm to predict and quantify 1572 cell line specific novel isoforms. Combined with seed enrichment analysis, we predicted 51 novel microRNA-155 isoform targets. Our work is among the first computational studies advocating the isoform-level microRNA target prediction.
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Project description:BackgroundIneffective erythropoiesis (IE) is the primary cause of anemia and associated pathologies in β-thalassemia. The characterization of IE is imbalance of erythroid proliferation and differentiation, resulting in increased erythroblast proliferation that fails to differentiate and gives rise to enucleate RBCs. MicroRNAs (miRs) are known to play important roles in hematopoiesis. miR-155 is a multifunctional molecule involved in both normal and pathological hematopoiesis, and its upregulation is observed in patients with β-thalassemia/HbE. However, the expression and function of miR-155, especially in β-thalassemia, have not yet been explored.MethodsTo study miR-155 expression in thalassemia, erythroblast subpopulations, CD45-CD71+Ter-119+ and CD45-CD71-Ter-119+ were collected from β IVSII-654 thalassemic bone marrow. Additionally, a two-phase culture of mouse bone marrow erythroid progenitor cells was performed. Expression of miR-155 and predicted mRNA target genes, c-myc, bach-1 and pu-1, were determined by quantitative reverse transcription (qRT)-polymerase chain reaction (PCR) and normalized to small nucleolar RNA (snoRNA) 202 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), respectively. To investigate the effect of miR-155 expression, erythroblasts were transfected with miR-inhibitor and -mimic in order to elevate and eliminate miR-155 expression, respectively. Erythroid cell differentiation was evaluated by Wright-Giemsa staining and flow cytometry.ResultsmiR-155 was upregulated, both in vivo and in vitro, during erythropoiesis in β-thalassemic mice. Our study revealed that gain- and loss of function of miR-155 were involved in erythroid proliferation and differentiation, and augmented proliferation and differentiation of thalassemic mouse erythroblasts may be associated with miR-155 upregulation. miR-155 upregulation in β-thalassemic mice significantly increased the percentage of basophilic and polychromatic erythroblasts. Conversely, a significant decrease in percentage of basophilic and polychromatic erythroblasts was observed in β-thalassemic mice transfected with anti-miR-155 inhibitor. We also examined the mRNA targets (c-myc, bach-1 and pu-1) of miR-155, which indicated that c-myc is a valid target gene of miR-155 that regulates erythroid differentiation.ConclusionmiR-155 regulates IE in β-thalassemia via c-myc expression controlling erythroblast proliferation and differentiation.
| S-EPMC11418816 | biostudies-literature
Project description:MicroRNA-155 (miR-155) has been as an important controller of TLR3 signalling. However, the interactions between miR-155 and TLR3 are poorly understood. Here, we focused on the regulation of the relationship between miR-155 and TLR3. Sequence analyses and firefly luciferase reporter assay revealed that miR-155 target were present in the coding sequences (CDS) of TLR3. And the expression of the TLR3 protein could be inhibited by a miR-155 mimic or by a virally encoded orthologue in chick embryo fibroblast cells. Notably, endogenous miR-155 induction emerged a negative regulation on TLR3 expression in TLR2, 4 and 7 ligands stimulated HD11 cells, an avian macrophage cell line. Moreover, treatment with the miR-155 antagomir increased TLR3 levels while significantly decreased the abundance of TLR3 with miR-155 agomir. In addition, our data showed that miR-155 could inhibit IFN-β production possibly though TLR3 signal pathway. All these findings might reveal a new mechanism by which miR-155 can regulate the TLR3 immune response.
| S-EPMC4418834 | biostudies-literature
Project description:MicroRNAs (miRNAs) are small non-coding RNAs that fine-tune the cell response to a changing environment by modulating the cell transcriptome. miR-155 is a multifunctional miRNA enriched in cells of the immune system and is indispensable for the immune response. However, when deregulated, miR-155 contributes to the development of chronic inflammation, autoimmunity, cancer, and fibrosis. Herein, we review the evidence for the pathogenic role of miR-155 in driving aberrant activation of the immune system in rheumatoid arthritis, and its potential as a disease biomarker and therapeutic target.
| S-EPMC5760508 | biostudies-literature
Project description:BackgroundGroup 2 innate lymphoid cells (ILC2s) are the most dominant ILCs in heart tissue, and sex-related differences exist in mouse lung ILC2 phenotypes and functions; however, it is still unclear whether there are sex differences in heart ILC2s.ResultsCompared with age-matched wild-type (WT) male mice, 8-week-old but not 3-week-old WT female mice harbored an obviously greater percentage and number of heart ILC2s in homeostasis. However, the percentage of killer-cell lectin-like receptor G1 (Klrg1)- ILC2s was higher, but the Klrg1+ ILC2s were lower in female mice than in male mice in both heart tissues of 3- and 8-week-old mice. Eight-week-old Rag2-/- mice also showed sex differences similar to those of age-matched WT mice. Regarding surface marker expression, compared to age-matched male mice, WT female mice showed higher expression of CD90.2 and Ki67 and lower expression of Klrg1 and Sca-1 in heart total ILC2s. There was no sex difference in IL-4 and IL-5 secretion by male and female mouse heart ILC2s. Increased IL-33 mRNA levels within the heart tissues were also found in female mice compared with male mice. By reanalyzing published single-cell RNA sequencing data, we found 2 differentially expressed genes between female and male mouse heart ILC2s. Gene set variation analysis revealed that the glycine, serine and threonine metabolism pathway was upregulated in female heart ILC2s. Subcluster analysis revealed that one cluster of heart ILC2s with relatively lower expression of Semaphorin 4a and thioredoxin interacting protein but higher expression of hypoxia-inducible lipid droplet-associated.ConclusionsThese results revealed greater numbers of ILC2s, higher expression of CD90.2, reduced Klrg1 and Sca-1 expression in the hearts of female mice than in male mice and no sex difference in IL-4 and IL-5 production in male and female mouse heart ILC2s. These sex differences in heart ILC2s might be due to the heterogeneity of IL-33 within the heart tissue.
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Project description:Innate lymphoid cells are central to the regulation of immunity at mucosal barrier sites, with group 2 innate lymphoid cells (ILC2s) being particularly important in type 2 immunity. In this study, we demonstrate that microRNA(miR)-142 plays a critical, cell-intrinsic role in the homeostasis and function of ILC2s. Mice deficient for miR-142 expression demonstrate an ILC2 progenitor-biased development in the bone marrow, and along with peripheral ILC2s at mucosal sites, these cells display a greatly altered phenotype based on surface marker expression. ILC2 proliferative and effector functions are severely dysfunctional following Nippostrongylus brasiliensis infection, revealing a critical role for miR-142 isoforms in ILC2-mediated immune responses. Mechanistically, Socs1 and Gfi1 expression are regulated by miR-142 isoforms in ILC2s, impacting ILC2 phenotypes as well as the proliferative and effector capacity of these cells. The identification of these novel pathways opens potential new avenues to modulate ILC2-dependent immune functions.
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Project description: Not available
| S-EPMC3915901 | biostudies-literature
Project description:MicroRNA 155 (miR-155) is involved in immune and inflammatory diseases and is associated with liver fibrosis and steatohepatitis. However, the mechanisms involved in miR-155 regulation of liver injury are largely unknown. The role of miR-155 in acute liver injury was assessed in wild-type (WT), miR-155-/- , and miR-155-/- mice transplanted with WT bone marrow. Additionally, miR-155 expression was evaluated in liver tissue and peripheral blood mononuclear cells of patients with autoimmune hepatitis. Concanavalin A, but not acetaminophen, treatment increased the expression of miR-155 in liver tissue of WT mice. Concanavalin A induced increases in cell death, liver aminotransferases, and expression of proinflammatory cytokines (chemokine [C-X-C motif] ligands 1, 5, 9, 10, and 11; chemokine [C-C motif] ligands 2 and 20; and intercellular cell adhesion molecule 1) in miR-155-/- compared to WT mice. Importantly, these animals showed a significant decrease in cluster of differentiation 4-positive/chemokine (C-X-C motif) receptor 3-positive and forkhead box p3-positive cell recruitment but no changes in other inflammatory cell populations. Mechanistically, miR-155-deficient regulatory T cells showed increased SH2 domain-containing inositol 5-phosphatase 1 expression, a known target of miR-155. Inhibition of SH2 domain-containing inositol 5-phosphatase 1 in miR-155-/- mice restored forkhead box p3 recruitment and reduced liver cytokine expression. Transplantation of bone marrow from WT animals into miR-155-/- mice partially reversed the effect of concanavalin A on miR-155-/- mice as assessed by proinflammatory cytokines and cell death protein expression. Patients with autoimmune hepatitis showed a marked increase in miR-155 expression in the liver but reduced expression of miR-155 in peripheral blood mononuclear cells. CONCLUSION:miR-155 expression is altered in both liver tissue and circulating inflammatory cells during liver injury, thus regulating inflammatory cell recruitment and liver damage; these results suggest that maintaining miR-155 expression in inflammatory cells might be a potential strategy to modulate liver injury. (Hepatology 2018).
| S-EPMC6082738 | biostudies-literature