Calcineurin-nuclear factor of activated T cells (CN-NFAT) inhibitors are widely clinically used drugs for immunosuppression, but besides their required T cell response inhibition, they also undesirably affect innate immune cells. Disruption of innate immune cell function can explain the observed susceptibility of CN-NFAT inhibitor-treated patients to opportunistic fungal infections. Neutrophils play an essential role in innate immunity as a defense against pathogens; however, the effect of CN-NFAT inhibitors on neutrophil function was poorly described. Thus, we tested the response of human neutrophils to opportunistic fungal pathogens, namely Candida albicans and Aspergillus fumigatus, in the presence of CN-NFAT inhibitors. Here, we report that the NFAT pathway members were expressed in neutrophils and mediated part of the neutrophil response to pathogens. Upon pathogen exposure, neutrophils underwent profound transcriptomic changes with subsequent production of effector molecules. Importantly, genes and proteins involved in the regulation of the immune response and chemotaxis, including the chemokines CCL2, CCL3, and CCL4 were significantly upregulated. The presence of CN-NFAT inhibitors attenuated the expression of these chemokines and impaired the ability of neutrophils to chemoattract other immune cells. Our results amend knowledge about the impact of CN-NFAT inhibition in human neutrophils.

Department of Biology Faculty of Medicine Masaryk University Brno Kamenice 753 5 Brno 625 00 Czech Republic

Institute of Hematology and Blood Transfusion U Nemocnice 2094 1 Prague 2 128 00 Czech Republic

International Clinical Research Center Faculty of Medicine Masaryk University Kamenice 753 5 Brno 625 00 Czech Republic

International Clinical Research Center St Anne's University Hospital Pekařská 664 53 Brno 602 00 Czech Republic

Section of Immunology and General Pathology Department of Medicine and Surgery University of Perugia Piazza Lucio Severi 1 8 Perugia 06132 Italy

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