NFAT signaling in human mesenchymal stromal cells affects extracellular matrix remodeling and antifungal immune responses

Federico Tidu; Marco De Zuani; Shyam Sushama Jose; Kamila Bendíčková; Lukáš Kubala; Frank Caruso; Francesca Cavalieri; Giancarlo Forte; Jan Frič

doi:10.1016/j.isci.2021.102683

NFAT signaling in human mesenchymal stromal cells affects extracellular matrix remodeling and antifungal immune responses

iScience. 2021 Jun 4;24(6):102683. doi: 10.1016/j.isci.2021.102683. eCollection 2021 Jun 25.

Authors

Federico Tidu^{1

2}, Marco De Zuani¹, Shyam Sushama Jose¹, Kamila Bendíčková¹, Lukáš Kubala^{1

3}, Frank Caruso⁴, Francesca Cavalieri⁴, Giancarlo Forte¹, Jan Frič^{1

5}

Affiliations

¹ International Clinical Research Center, St. Anne's University Hospital, Pekařská 53, 656 91 Brno, Czech Republic.
² Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.
³ Institute of Biophysics of the Czech Academy of Sciences, Kralovopolska 135, 612 65 Brno, Czech Republic.
⁴ ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, and the Department of Chemical Engineering, University of Melbourne, Parkville, VIC 3010, Australia.
⁵ Institute of Hematology and Blood Transfusion, U Nemocnice 2094/1, 128 20 Prague, Czech Republic.

Abstract

Mesenchymal stromal cells (MSCs) combined with calcineurin-nuclear factor of activated T cell (CN-NFAT) inhibitors are being tested as a treatment for graft-versus-host disease (GvHD). The immunosuppressive properties of MSCs seem beneficial; however, their response during fungal infection, which is an important cause of mortality in patients with GvHD , is unknown. We report that MSCs phagocytose the fungal component zymosan, resulting in phosphorylation of spleen tyrosine kinase (Syk), increase in cytosolic calcium levels, and ultimately, increase in NFAT1 nuclear translocation. RNA sequencing analysis of zymosan-treated MSCs showed that CN-NFAT inhibition affects extracellular matrix (ECM) genes but not cytokine expression that is under the control of the NF-κB pathway. When coculturing MSCs or decellularized MSC-ECM with human peripheral blood mononuclear cells (PBMCs), selective NFAT inhibition in MSCs decreased cytokine expression by PBMCs. These findings reveal a dual mechanism underlying the MSC response to zymosan: while NF-κB directly controls inflammatory cytokine expression, NFAT impacts immune-cell functions by regulating ECM remodeling.

Keywords: Immunology; Mycology.