Human Mast Cells and Mastocytosis: Harnessing MicroRNA Expression as a New Approach to Therapy?

MicroRNAs (miRNAs) are short, non-coding RNAs that have emerged as key post-transcriptional regulators in a wide variety of organisms and critical cellular processes. Because any one miRNA can regulate the expression of a distinct set of genes, differential miRNA expression can shape the repertoire of proteins that are actually expressed during development, differentiation, or disease. To understand what goes wrong when a cell becomes transformed requires knowledge of the processes that ensure normal development. It is now clear that miRNAs may act as oncogenes and/or tumor suppressors within gene regulatory networks, thereby contributing to the development of cancer. Mast cells are long-lived cells, widely distributed throughout vascularized tissues, in particular near surfaces that are exposed to the environment (such as skin, airways, and the gastrointestinal tract), where they contribute to bacterial clearance, enhancement of adaptive immune responses, modulation of inflammation, and the degradation of toxic peptides and venoms. Here we review current knowledge in the field of mast-cell differentiation and disease in humans and mice and discuss future directions and links between mast-cell differentiation, oncogenic transformation, and microRNAs as well as possible new points of entry for therapeutic interventio

Macrophage Activation: Glancing into Diversity

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MiR-146a in Immunity and Disease

MicroRNAs (miRNAs) are regulatory molecules able to influence all aspects of the biology of a cell. They have been associated with diseases such as cancer, viral infections, and autoimmune diseases, and in recent years, they also emerged as important regulators of immune responses. MiR-146a in particular is rapidly gaining importance as a modulator of differentiation and function of cells of the innate as well as adaptive immunity. Given its importance in regulating key cellular functions, it is not surprising that miR-146a expression was also found dysregulated in different types of tumors. In this paper, we summarize recent progress in understanding the role of miR-146a in innate and adaptive immune responses, as well as in disease

Epigenetic and transcriptional control of mast cell responses

Mast cells are tissue-resident, innate immune cells present in most tissues of the body and are important effector and immunomodulatory cells. Differentiated mast cells typically are characterized by the surface expression of the receptors KIT and FcεRI, the latter especially being important for stimulation through IgE antibodies, although these cells have the ability to respond to a wide variety of environmental signals, to which they can variably react by releasing pre-stored or de novo–synthesized mediators or both. Since mast cells terminate their differentiation in their tissue of residence in response to specific microenvironmental cues, each tissue may comprise unique mast cell subtypes, and responses are tailored to the danger signals that are likely to be encountered in each anatomical location. From a transcriptional point of view, these cells therefore must be endowed with epigenetic and transcriptional programs that allow them to maintain a stable identity and at the same time allow sufficient plasticity to adapt to different environmental challenges. In this commentary, we highlight some of the recent findings that advanced our understanding of the transcriptional and epigenetic programs regulating mast cell functions

MiR-146a in immunity and disease

MicroRNAs (miRNAs) are regulatory molecules able to influence all aspects of the biology of a cell. They have been associated with diseases such as cancer, viral infections, and autoimmune diseases, and in recent years, they also emerged as important regulators of immune responses. MiR-146a in particular is rapidly gaining importance as a modulator of differentiation and function of cells of the innate as well as adaptive immunity. Given its importance in regulating key cellular functions, it is not surprising that miR-146a expression was also found dysregulated in different types of tumors. In this paper, we summarize recent progress in understanding the role of miR- 146a in innate and adaptive immune responses, as well as in disease

MicroRNAs in hematopoietic development

Background: MicroRNAs (miRNAs) are short non-coding RNAs involved in the posttranscriptional regulation of a wide range of biological processes. By binding to complementary sequences on target messenger RNAs, they trigger translational repression and degradation of the target, eventually resulting in reduced protein output. MiRNA-dependent regulation of protein translation is a very widespread and evolutionarily conserved mechanism of posttranscriptional control of gene expression. Accordingly, a high proportion of mammalian genes are likely to be regulated by miRNAs. In the hematopoietic system, both transcriptional and posttranscriptional regulation of gene expression ensure proper differentiation and function of stem cells, committed progenitors as well as mature cells. Results : In recent years, miRNA expression profiling of various cell types in the hematopoietic system, as well as gene-targeting approaches to assess the function of individual miRNAs, revealed the importance of this type of regulation in the development of both innate and acquired immunity. Conclusions : We discuss the general role of miRNA biogenesis in the development of hematopoietic cells, as well as specific functions of individual miRNAs in stem cells as well as in mature immune cells

MiR-221 influences effector functions and actin cytoskeleton in mast cells.

Mast cells have essential effector and immunoregulatory functions in IgE-associated allergic disorders and certain innate and adaptive immune responses, but the role of miRNAs in regulating mast cell functions is almost completely unexplored. To examine the role of the activation-induced miRNA miR-221 in mouse mast cells, we developed robust lentiviral systems for miRNA overexpression and depletion. While miR-221 favored mast cell adhesion and migration towards SCF or antigen in trans-well migration assays, as well as cytokine production and degranulation in response to IgE-antigen complexes, neither miR-221 overexpression, nor its ablation, interfered with mast cell differentiation. Transcriptional profiling of miR-221-overexpressing mast cells revealed modulation of many transcripts, including several associated with the cytoskeleton; indeed, miR-221 overexpression was associated with reproducible increases in cortical actin in mast cells, and with altered cellular shape and cell cycle in murine fibroblasts. Our bioinformatics analysis showed that this effect was likely mediated by the composite effect of miR-221 on many primary and secondary targets in resting cells. Indeed, miR-221-induced cellular alterations could not be recapitulated by knockdown of one of the major targets of miR-221. We propose a model in which miR-221 has two different roles in mast cells: in resting cells, basal levels of miR-221 contribute to the regulation of the cell cycle and cytoskeleton, a general mechanism probably common to other miR-221-expressing cell types, such as fibroblasts. Vice versa, upon induction in response to mast cell stimulation, miR-221 effects are mast cell-specific and activation-dependent, contributing to the regulation of degranulation, cytokine production and cell adherence. Our studies provide new insights into the roles of miR-221 in mast cell biology, and identify novel mechanisms that may contribute to mast cell-related pathological conditions, such as asthma, allergy and mastocytosis

Epigenetics of T lymphocytes in health and disease

The risk of developing autoimmune diseases depends on both genetic and environmental factors, with epigenetic mechanisms of regulation potentially translating environmental cues into stable modifications in gene expression. Such stable memory of a functional state has been deciphered into a number of molecular mechanisms that collectively define the epigenetic status of a cell. In recent years, it has become increasingly clear that epigenetic modifications are highly dynamic and are able to adapt to the changing environment, with important impact on the onset and development of a number of diseases. Here, we describe some of the epigenetic mechanisms of regulation of cellular functional states in T lymphocytes, with a particular focus on DNA methylation. We will also discuss current knowledge on the role of epigenetics in autoimmunity and consider open questions in the field

Uncoupling protein 2 G(-866)A polymorphism: a new gene polymorphism associated with C-reactive protein in type 2 diabetic patients C-reactive protein in type 2 diabetic patients

<p>Abstract</p> <p>Background</p> <p>This study evaluated the relationship between the G(-866)A polymorphism of the uncoupling protein 2 (UCP2) gene and high-sensitivity C reactive protein (hs-CRP) plasma levels in diabetic patients.</p> <p>Methods</p> <p>We studied 383 unrelated people with type 2 diabetes aged 40-70 years. Anthropometry, fasting lipids, glucose, HbA1c, and hs-CRP were measured. Participants were genotyped for the G (-866)A polymorphism of the uncoupling protein 2 gene.</p> <p>Results</p> <p>Hs-CRP (mg/L) increased progressively across the three genotype groups AA, AG, or GG, being respectively 3.0 ± 3.2, 3.6 ± 5.0, and 4.8 ± 5.3 (p for trend = 0.03). Since hs-CRP values were not significantly different between AA and AG genotype, these two groups were pooled for further analyses. Compared to participants with the AA/AG genotypes, homozygotes for the G allele (GG genotype) had significantly higher hs-CRP levels (4.8 ± 5.3 vs 3.5 ± 4.7 mg/L, p = 0.01) and a larger proportion (53.9% vs 46.1%, p = 0.013) of elevated hs-CRP (> 2 mg/L). This was not explained by major confounders such as age, gender, BMI, waist circumference, HbA1c, smoking, or medications use which were comparable in the two genotype groups.</p> <p>Conclusions</p> <p>The study shows for the first time, in type 2 diabetic patients, a significant association of hs-CRP levels with the G(-866)A polymorphism of UCP2 beyond the effect of major confounders.</p