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Front. Immunol. | doi: 10.3389/fimmu.2018.03111

Amplified host defense by Toll-like receptor-mediated downregulation of the glucocorticoid-induced leucine zipper (GILZ) in macrophages

 Jessica Hoppstädter1*,  Britta Diesel1, Nina Hachenthal1, Marie Minet1, Petra Leidinger2, Christina Backes1, Friedrich Grässer2, Eckart Meese2,  Stefano Bruscoli3,  Carlo Riccardi3,  Hanno Huwer4 and  Alexandra K. Kiemer1
  • 1Saarland University, Germany
  • 2Universitätsklinikum des Saarlandes, Germany
  • 3University of Perugia, Italy
  • 4HerzZentrum Saar, Germany

Activation of toll-like receptors (TLRs) plays a pivotal role in the host defense against bacteria and results in the activation of NF-B-mediated transcription of proinflammatory mediators. Glucocorticoid-induced leucine zipper (GILZ) is an anti-inflammatory mediator, which inhibits NF-B activity in macrophages. Thus, we aimed to investigate the regulation and role of GILZ expression in primary human and murine macrophages upon TLR activation.
Treatment with TLR agonists, e.g., Pam3CSK4 (TLR1/2) or LPS (TLR4) rapidly decreased GILZ mRNA and protein levels. In consequence, GILZ downregulation led to enhanced induction of pro-inflammatory mediators, increased phagocytic activity, and a higher capacity to kill intracellular bacteria (Salmonella enterica serovar typhimurium), as shown in GILZ knockout macrophages.
Treatment with the TLR3 ligand polyinosinic:polycytidylic acid (Poly(I:C)) did not affect GILZ mRNA levels, although GILZ protein expression was decreased. This effect was paralleled by sensitization towards TLR1/2- and TLR4-agonists.
A bioinformatics approach implicated more than 250 miRNAs as potential GILZ regulators. Microarray analysis revealed that the expression of several potentially GILZ-targeting miRNAs was increased after Poly(I:C) treatment in primary human macrophages. We tested the ability of 11 of these miRNAs to target GILZ by luciferase reporter gene assays. Within this small set, four miRNAs (hsa-miR-34b*, -222, -320d, -484) were confirmed as GILZ regulators, suggesting that GILZ downregulation upon TLR3 activation is a consequence of the synergistic actions of multiple miRNAs.
In summary, our data show that GILZ downregulation promotes macrophage activation. GILZ downregulation occurs both via MyD88-dependent and -independent mechanisms and can involve decreased mRNA or protein stability and an attenuated translation.

Keywords: Inflammation, TLR - toll-like receptor, TRIF, MyD88, NF-k B, nuclear factor-k B, Cytokine - immunological terms, Phagocytosis, Salmonella

Received: 23 Aug 2018; Accepted: 17 Dec 2018.

Edited by:

Alexandre Corthay, Department of Pathology, Oslo University Hospital, Norway

Reviewed by:

Philippe Georgel, Université de Strasbourg, France
Kishore Kumar Jella, Emory University, United States
Esmaeil Mortaz, National Research instituteTuberculosis and lung diseases, Iran  

Copyright: © 2018 Hoppstädter, Diesel, Hachenthal, Minet, Leidinger, Backes, Grässer, Meese, Bruscoli, Riccardi, Huwer and Kiemer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Jessica Hoppstädter, Saarland University, Saarbrücken, Germany, jhoppstaedter@gmx.de