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

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

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

miR-146a and NF-κB1 regulate mast cell survival and T lymphocyte differentiation

The transcription factor NF-κB regulates the expression of a broad number of genes central to immune and inflammatory responses. We identified a new molecular network that comprises specifically the NF-κB family member NF-κB1 (p50) and miR-146a, and we show that in mast cells it contributes to the regulation of cell homeostasis and survival, while in T lymphocytes it modulates T cell memory formation. Increased mast cell survival was due to unbalanced expression of pro- and antiapoptotic factors and particularly to the complete inability of p50- deleted mast cells to induce expression of miR-146a, which in the context of mast cell survival acted as a proapoptotic factor. Interestingly, in a different cellular context, namely, human and mouse primary T lymphocytes, miR-146a and NF-κB p50 did not influence cell survival or cytokine production but rather T cell expansion and activation in response to T cell receptor (TCR) engagement. Our data identify a new molecular network important in modulating adaptive and innate immune responses and show how the same activation-induced microRNA (miRNA) can be similarly regulated in different cell types even in response to different stimuli but can still determine very different outcomes, likely depending on the specific transcriptome

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

MiR-146a: a key microRNA involved in regulating mast cell survival and T lymphocyte differentiation

Mast cells are long-lived, tissue-resident cells of the innate immune system. Since the identification of mechanisms that regulate mast cell proliferation, survival and overall homeostasis in the tissues may have important implications for the treatment of mast cell-related diseases such as asthma, allergy and mastocytosis, we investigated novel molecular mechanisms at the basis of mast cell biology, and in particular the role of two activation-induced miRNAs, miR-221 and miR-146a. We found that miR-221 has important roles in regulating multiple processes in differentiated primary mast cells, such as degranulation, adhesion, migration and cytokine production. Since miR-221 is expressed at basal level in mast cells but it is also inducible upon stimulation, we proposed a model in which miR-221 has a dual role in these cells: at resting state, it contributes to the regulation of the cell cycle and cytoskeleton, an effect probably common also to other cell types that express basal levels of this miRNA. However, in response to stimulation through IgE-antigen complexes, miR-221 effects are mast cell-specific and activation-dependent, contributing to the regulation of degranulation, cytokine production and cell adherence (Chapter 1). Mice that lack the p50 subunit of NF-kB (p50KO) are unable to mount airway eosinophilic inflammation due to the inability to produce IL-4, IL-5 and IL-13, which play distinct roles in asthma pathogenesis, and to a defect in the polarization of Th2 lymphocytes. Since mast cells are master effector cells in allergic responses, we evaluated whether the asthma-resistant phenotype observed in p50KO mice could be partially due to a defect in mast cell development or function. While our data indicate that p50KO mast cells may only marginally contribute to the airway inflammation defect of p50KO mice through a slight impairment in cytokine production, p50KO mast cells showed a marked increase in their ability to survive in response to withdrawal of essential cytokines, which likely correlated with a strong increase in the percentage of mast cells that was observed in the tissues of p50KO animals. Such improved survival of mast cells lacking p50 was due to altered expression of several molecules involved in regulating cell survival and cell death, such as Bcl2, A1 and BAX. Importantly, we also found that miR-146a, a miRNA known to regulate NF-kB signalling, was not expressed in IgE- or LPS-stimulated p50KO mast cells, and that in the context of mast cell survival, miR-146a acted as a pro-apoptotic factor, identifying therefore a new molecular network that regulates mast cell survival in response to a variety of signals (Chapter 2). Previous work from our lab also pointed toward a role for miR-146a in the differentiation and/or activation of murine CD4 T lymphocytes. We therefore continued investigating a possible role for this miRNA not only in regulating mast cell survival, but also in the differentiation and function of T cells. We found that miR-146a is expressed at high levels in the effector and effector-memory T cell compartment in both mouse and human, and we provide evidences that miR-146a may regulate T cell expansion upon activation and possibly also memory formation (Chapter 3). A review on the role of miR-146a in immunity and disease is provided in Chapter 4. Overall our work demonstrates that miR-221 and miR-146a play a key role in regulating mast cell activation, function and survival, and that miR-146a also contributes to the extent of T lymphocyte activation. Finally, we provide novel insights on the role of miRNAs in regulating various functions of mast cells and T lymphocytes in the immune response, contributing to the groundwork for a further understanding of the molecular mechanisms that may lead to immune-related diseases such as asthma, allergy, altered inflammatory responses, and mastocytosis

Assessment of bioaerosols and inhalable dust exposure in Swiss sawmills

An assessment of wood workers' exposure to airborne cultivable bacteria, fungi, inhalable endotoxins and inhalable organic dust was performed at 12 sawmills that process mainly coniferous wood species. In each plant, samples were collected at four or five different work sites (debarking, sawing, sorting, planing and sawing cockpit) and the efficiency of sampling devices (impinger or filter) for determining endotoxins levels was evaluated. Results show that fungi are present in very high concentrations (up to 35 000 CFU m(-3)) in all sawmills. We also find that there are more bioaerosols at the sorting work site (mean +/- SD: 7723 +/- 9919 CFU m(-3) for total bacteria, 614 +/- 902 CFU m(-3) for Gram-negative, 19 438 +/- 14 246 CFU m(-3) for fungi, 7.0 +/- 9.0 EU m(-3) for endotoxin and 2.9 +/- 4.8 g m(-3) for dust) than at the sawing station (mean +/- SD: 1938 +/- 2478 CFU m(-3) for total bacteria, 141 +/- 206 CFU m(-3) for Gram-negative, 12 207 +/- 10 008 CFU m(-3) for fungi, 2.1 +/- 1.9 EU m(-3) for endotoxin and 0.75 +/- 0.49 mg m(-3) for dust). At the same time, the species composition and concentration of airborne Gram-negative bacteria were studied. Penicillinium sp. were the predominant fungi, while Bacillus sp. and the Pseudomonadacea family were the predominant Gram-positive and Gram-negative bacteria encountered, respectively. [Authors]]]> eng oai:serval.unil.ch:BIB_A3A78709CE2D 2022-02-19T02:27:47Z openaire documents <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_A3A78709CE2D Between stuckness and stillness: Why do young adults not undertake temporary mobility? info:doi:10.1002/psp.2461 info:eu-repo/semantics/altIdentifier/doi/10.1002/psp.2461 Haldimann, Lucas Heers, Marieke Rérat, Patrick info:eu-repo/semantics/article article 2021-03-07 Population, Space and Place, vol. 27, no. 8 info:eu-repo/semantics/altIdentifier/pissn/1544-8444 info:eu-repo/semantics/altIdentifier/pissn/1544-8452 <![CDATA[Youth temporary mobility occurs for purposes such as volunteering, Erasmus exchanges and linguistic stays. Although it is increasingly common, a large proportion of young adults are not mobile. This study is based on a large‐scale survey among young adults in Switzerland. It draws on the concept of motility to analyse the barriers to temporary mobility, where motility may be defined as a set of mobility resources that refer to three dimensions: access (e.g., financial means or time), skills (e.g., languages and self‐confidence) and appropriation (e.g., level of interest). A typology places nonmobile young adults on a continuum between ‘stillness’ (no desire to move) and ‘stuckness’ (unable to move) and identifies four groups: ‘the constrained’ and ‘the financially challenged’ are often constrained to a varying extent by their socio‐economic background, their educational pathways and their family network. ‘The locally anchored’ and especially ‘the satisfied stayers’ face fewer constraints and draw more on their own agency to be nonmobile