Erola Ainsua-Enrich

University of Barcelona, Barcino, Catalonia, Spain

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Publications (5)22.92 Total impact

  • Sandra Bajaña · Sean Turner · Jinny Paul · Erola Ainsua-Enrich · Susan Kovats
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    ABSTRACT: Dendritic cells (DCs) initiate immune responses in barrier tissues including lung and skin. Conventional DC (cDC) subsets, CD11b(-) (cDC1s) or CD11b(+) (cDC2s), arise via distinct networks of transcription factors involving IFN regulatory factor 4 (IRF4) and IRF8, and are specialized for unique functional responses. Using mice in which a conditional Irf4 or Irf8 allele is deleted in CD11c(+) cells, we determined whether IRF4 or IRF8 deficiency beginning in CD11c(+) cDC precursors (pre-cDCs) changed the homeostasis of mature DCs or pre-DCs in the lung, dermis, and spleen. CD11c-cre-Irf4(-/-) mice selectively lacked a lung-resident CD11c(hi)CD11b(+)SIRPα(+)CD24(+) DC subset, but not other lung CD11b(+) DCs or alveolar macrophages. Numbers of CD11b(+)CD4(+) splenic DCs, but not CD11b(+) dermal DCs, were reduced, indicating cDC2s in the lung and dermis develop via different pathways. Irf4 deficiency did not alter numbers of cDC1s. CD11c-cre-Irf8(-/-) mice lacked lung-resident CD103(+) DCs and splenic CD8α(+) DCs, yet harbored increased IRF4-dependent DCs. This correlated with a reduced number of Irf8(-/-) pre-cDCs, which contained elevated IRF4, suggesting that Irf8 deficiency diverts pre-cDC fate. Analyses of Irf4 and Irf8 haploinsufficient mice showed that, although one Irf4 allele was sufficient for lung cDC2 development, two functional Irf8 alleles were required for differentiation of lung cDC1s. Thus, IRF8 and IRF4 act in pre-cDCs to direct the terminal differentiation of cDC1 and cDC2 subsets in the lung and spleen. These data suggest that variation in IRF4 or IRF8 levels resulting from genetic polymorphisms or environmental cues will govern tissue DC numbers and, therefore, regulate the magnitude of DC functional responses.
    No preview · Article · Jan 2016 · The Journal of Immunology
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    ABSTRACT: SH3-binding protein 2 (3BP2) is a cytoplasmic adaptor protein that acts as a positive regulator in mast cell FcεRI-dependent signaling. The KIT receptor whose ligand is the stem cell factor is necessary for mast cell development, proliferation, and survival as well as for optimal IgE-dependent signal. Activating mutations in KIT have been associated with several diseases including mastocytosis. In the present work, we found that 3BP2 silencing impairs KIT signaling pathways, thus affecting phosphoinositide 3-kinase and MAPK pathways in human mast cells (huMCs) from HMC-1, LAD2 (huMC lines), and CD34(+)-derived mast cells. Unexpectedly, silencing of 3BP2 reduces KIT expression in normal huMCs as well as in HMC-1 cells where KIT is mutated, thus increasing cellular apoptosis and caspase-3/7 activity. 3BP2 silencing reduces KIT transcription expression levels. Interestingly, 3BP2 silencing decreased microphthalmia-associated transcription factor (MITF) expression, a transcription factor involved in KIT expression. Reconstitution of 3BP2 in knockdown cells leads to reversal of KIT expression as well as survival phenotype. Accordingly MITF reconstitution enhances KIT expression levels in 3BP2-silenced cells. Moreover, downregulation of KIT expression by miRNA-221 overexpression or the proteasome inhibitor bortezomib also reduced 3BP2 and MITF expression. Furthermore, KIT tyrosine activity inhibition reduced 3BP2 and MITF expression, demonstrating again a tight and reciprocal relationship between these molecules. Taken together, our results show that 3BP2 regulates huMC survival and participates in KIT-mediated signal transduction by directly controlling KIT receptor expression, suggesting its potential as a therapeutic target in mast cell-mediated inflammatory diseases and deregulated KIT disorders. Copyright © 2015 by The American Association of Immunologists, Inc.
    Full-text · Article · Mar 2015 · The Journal of Immunology
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    ABSTRACT: Mast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle to cause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the refractory period observed in patients with EIB.
    Full-text · Article · Oct 2014 · PLoS ONE
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    ABSTRACT: Adaptor molecules are essential in organizing signaling molecules and in coordinating and compartmentalizing their activity. SH3-binding protein 2 (3BP2) is a cytoplasmic adaptor protein mainly expressed by hematopoietic cells that has been shown to act as a positive regulator in T, B, and NK cell signal transduction. 3BP2 is an important regulator of cytotoxic granule release in NK cells. Mast cells (MCs) similarly degranulate following Ag-dependent aggregation of the FcεRI on the cell surface. Activation of these cells induces the release of preformed inflammatory mediators and the de novo synthesis and secretion of cytokines and chemokines. Thus, MCs participate in both innate and acquired responses. We observed that 3BP2 is expressed in human MCs (huMCs) from diverse origins. Moreover, 3BP2 coimmunoprecipitates with essential MC signaling mediators such as Lyn, Syk, and phospholipase C γ; thus, a role for this adaptor in MC function was postulated. In the present work, we used the short hairpin RNA lentiviral targeting approach to silence 3BP2 expression in huMCs. Our findings point to a requirement for 3BP2 in optimal immediate and late MCs responses such as degranulation and IL-8 or GM-CSF secretion. 3BP2 was determined to be necessary for optimal phosphorylation of Syk, linker for activation of T cells, and phospholipase C γ(1), critical signals for calcium release from intracellular stores. Taken together, our results show that by participating in FcεRI- mediated signal transduction 3BP2 is an important regulator of huMC activation. Thus, 3BP2 could be a potential therapeutic target for IgE-dependent MC-mediated inflammatory disease.
    Full-text · Article · Aug 2012 · The Journal of Immunology
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    ABSTRACT: CD84 is a self-binding receptor from the CD150 (or signaling lymphocyte activation molecule [SLAM]) family that is broadly expressed in hematopoietic cells. It has been described that the adaptors SLAM-associated protein (SAP) and EWS-FLI1-activated transcript 2 (EAT-2) are critical for CD150 family members' signaling and function. We observed that human mast cells express CD84 but lack SAP or EAT-2, that CD84 is tyrosine phosphorylated upon FcεRI engagement, and that the release of granule contents is reduced when FcεRI is coengaged with CD84 in LAD2 and human CD34(+)-derived mast cells. In addition, we observed that the release of IL-8 and GM-CSF was also reduced in FcεRI/CD84-costimulated cells as compared with FcεRI/Ig control. To understand how CD84 downregulates FcεRI-mediated function, we analyzed signaling pathways affected by CD84 in human mast cells. Our results showed that CD84 dampens FcεRI-mediated calcium mobilization after its co-cross-linking with the receptor. Furthermore, FcεRI-mediated Syk-linker for activation of T cells-phospholipase C-γ1 axis activity is downregulated after CD84 stimulation, compared with FcεRI/Ig control. The inhibitory kinase Fes phosphorylates mainly the inhibitory motif for CD84. Moreover, Fes, which has been described to become phosphorylated after substrate binding, also gets phosphorylated when coexpressed with CD84. Consistently, Fes was observed to be more phosphorylated after CD84 and FcεRI co-cross-linking. The phosphorylation of the protein phosphatase Src homology region 2 domain-containing phosphatase-1 also increases after CD84 and FcεRI coengagement. Taken together, our results show that CD84 is highly expressed in mast cells and that it contributes to the regulation of FcεRI signaling in SAP- and EAT-2-independent and Fes- and Src homology region 2 domain-containing phosphatase-1-dependent mechanisms.
    Full-text · Article · Nov 2011 · The Journal of Immunology

Publication Stats

21 Citations
22.92 Total Impact Points

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Institutions

  • 2011-2015
    • University of Barcelona
      Barcino, Catalonia, Spain
  • 2014
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain