Calcineurin inhibitors reduce NFAT-dependent expression of antifungal pentraxin-3 by human monocytes

Abstract

Calcineurin (CN) inhibitors are effective clinical immunosuppressants but leave patients vulnerable to potentially fatal fungal infections. This study tested the hypothesis that CN inhibition interferes with antifungal immune defenses mediated by monocytes. We showed that NFAT is expressed by human monocytes, and is activated by exposure to fungal ligands. We confirmed that NFAT translocation potently activated target gene transcription using a human monocytic reporter cell line. Inhibition of CN‐NFAT by cyclosporine A significantly reduced monocyte production of TNF‐α, IL‐10, and MCP‐1 proteins in response to pattern recognition receptor ligands as well as to Aspergillus fumigatus conidia. Moreover, we revealed that human monocytes express the antifungal protein pentraxin‐3 under control of NFAT. In conclusion, clinical CN inhibitors have the potential to interfere with the novel NFAT‐dependent pentraxin‐3 pathway as well as antifungal cytokine production in human monocytes, thereby impeding monocyte‐mediated defenses against fungal infection in immune‐suppressed patients.

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

“…These data thus support that Ad-MSCs adopt a PRR-driven response to zymosan that might result in NFAT activation. In fact, we and others have reported that the CN-NFAT pathway is engaged during the PRR-dependent antifungal response ( Bendíčková et al., 2020 ; Goodridge et al., 2007 ) ( Figure 2 F). To verify whether Ad-MSCs engage the CN-NFAT axis in response to zymosan, we again stimulated the cells using the particulate ligand and monitored NFAT subcellular localization by confocal microscopy.…”

Immunosuppression Affects Neutrophil Functions: Does Calcineurin-NFAT Signaling Matter?

“…CN-NFAT activation also occurs in human monocytes exposed to the ligand from Saccharomyces cerevisiae (S. cerevisiae) cell wall - zymosan ( 65 ), and similarly in murine macrophages and DCs after dectin-1 ligation by zymosan or live C. albicans ( 62 ). However, in macrophages exposed to A. fumigatus distinct pathway of TLR9- and phagocytosis-dependent NFAT activation mediated by Bruton’s tyrosine kinase (BTK), but independent on MyD88 has been reported ( 66 ).…”

“…These clinically successful CNI were also recently repurposed to treat autoimmune disorders [reviewed in ( 59 )] and as cancer chemotherapy considering that several cancer types have constitutively activated and overexpressed NFAT ( 73 , 74 ). However, counterbalancing their potentially beneficial therapeutic role, a growing body of evidence indicates the potential impact of these compounds on myeloid cell function, leading to increased susceptibility to infections ( 59 , 65 , 66 ).…”

Roles of IL-2 in bridging adaptive and innate immunity, and as a tool for cellular immunotherapy

“…Activated CN then dephosphorylates NFAT in the cytoplasm, causing a change in its conformation that exposes a nuclear translocation sequence, leading to initiation of transcription of target genes, including of il2 7,8 . What we now know is that this process does not occur only in T cells, but also in cells of the innate immune system, such as dendritic cells (DC), monocytes and NK cells 9 …”