Calcineurin-NFAT signaling controls the neutrophils´ ability of chemoattraction upon fungal infection.

Calcineurin-nuclear factor of activated T-cell (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 inhibitors-treated patients to opportunistic fungal infections. Neutrophils play a crucial role in the innate immunity pathogen defense, while however the effect of CN-NFAT inhibitors on neutrophil function is poorly described. Thus, we tested the response of human neutrophils to fungal pathogens, namely Candida albicans and Aspergillus fumigatus in the presence of CN-NFAT inhibitors. We report that the NFAT pathway members are expressed in neutrophils and mediates part of the neutrophil response to pathogens. Upon pathogen exposure, neutrophils underwent profound transcriptomic changes. Importantly, genes 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. Overall design: In order to investigate the effect of CN-NFAT inhibitors on neutrophil function we treated neutrophils from healthy donors with fungal pathogens with or without prior pretreatment with CN-NFAT inhibitor Cyclosporine A. Differential gene expression analysis from RNAseq data from neutrophils treated with CN-NFAT inhibitor Cyclosporine A and/or fungal pathogens.