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

• DOI: 10.1016/j.isci.2021.102683
• Publication Date: 2021-06-05T00:20:29Z
• Authors: Federico Tidu; Marco De Zuani; Shyam Sushama Jose; Kamila Bendíčková; Lukáš Kubala; Frank Caruso; Francesca Cavalieri; Giancarlo Forte; Jan Frič
• Keywords: NFAT; Proinflammatory cytokine

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