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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Molecular Innate Immunity
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1444558

Unveiling signaling pathways inducing MHC class II expression in neutrophils

Provisionally accepted
Pascal Forrer Pascal Forrer 1,2Darya Palianina Darya Palianina 1*Claudia Stühler Claudia Stühler 1Matthias Kreuzaler Matthias Kreuzaler 1,2Julien Roux Julien Roux 3,4Jiagui Li Jiagui Li 5David Burckhardt David Burckhardt 2,6Fabian Franzeck Fabian Franzeck 6Daniela Finke Daniela Finke 6Alexander Schmidt Alexander Schmidt 7Dirk Bumann Dirk Bumann 5Nina Khanna Nina Khanna 6,8*
  • 1 Department of Biomedicine, University Children’s Hospital Basel, Basel, Basel-Stadt, Switzerland
  • 2 Novartis (Switzerland), Basel, Switzerland
  • 3 Bioinformatics Core Facility, Department of Biomedicine, Faculty of Medicine, University of Basel, Basel, Switzerland
  • 4 Swiss Institute of Bioinformatics, University of Zurich, Lausanne, Switzerland
  • 5 University of Basel, Basel, Switzerland
  • 6 Department of Biomedicine, Faculty of Medicine, University of Basel, Basel, Switzerland
  • 7 Department of Biozentrum, Faculty of Science, University of Basel, Basel, Switzerland
  • 8 Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Basel, Basel, Switzerland

The final, formatted version of the article will be published soon.

    Gram-negative bacillary bacteremia poses a significant threat, ranking among the most severe infectious diseases capable of triggering life-threatening sepsis. Despite the unambiguous involvement of neutrophils in this potentially fatal disease, there are limited data about the molecular signaling mechanisms, phenotype, and function of human neutrophils during the early phase of gramnegative bacillary bacteremia. By using an unbiased proteomics and flow cytometry approach, we identified an antigen-presenting cell (APC)-like phenotype in human peripheral blood neutrophils (PMN) with MHC class II molecule expression in the early phase of bacteremia. Using an in-vitro model of GM-CSF-mediated induction of APC-like phenotype in PMN, we investigated downstream signaling pathways leading to MHC class II expression. GM-CSF stimulation of neutrophils leads to the activation of three major signaling pathways, the JAK-STAT, the mitogen-activated protein kinase (MAPK), and the phosphoinositide 3-kinase (PI3K)-Akt-mTOR pathways, while MHC class II induction is mediated by a MAPK-p38-MSK1-CREB1 signaling cascade and the MHC class II transactivator CIITA in a strictly JAK1/2 kinase-dependent manner. Our data describing details of signaling pathways inducing MHC class II expression in neutrophils open new possibilities of therapeutic targeting of JAK1/2 signaling during different stages of gram-negative bacteremia and sepsis.

    Keywords: innate immunity, Antigen-Presenting Cells, APC-like neutrophils, Gram-negative bacteremia, Sepsis, JAK-STAT signaling, MHC class II, GM-CSF

    Received: 05 Jun 2024; Accepted: 10 Sep 2024.

    Copyright: © 2024 Forrer, Palianina, Stühler, Kreuzaler, Roux, Li, Burckhardt, Franzeck, Finke, Schmidt, Bumann and Khanna. 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) or licensor 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:
    Darya Palianina, Department of Biomedicine, University Children’s Hospital Basel, Basel, 4056, Basel-Stadt, Switzerland
    Nina Khanna, Department of Biomedicine, Faculty of Medicine, University of Basel, Basel, Switzerland

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.