Abstract
Neutrophils are innate immune cells with important roles in antimicrobial defense. However, impaired or dysregulated neutrophil function can result in host tissue damage, loss of homeostasis, hyperinflammation or pathological immunosuppression. A central link between neutrophil activation and immune outcomes is emerging to be the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, which is activated by neutrophil detection of a microbial threat via pattern recognition receptors and results in inflammatory cytokine production. This potent pro-inflammatory pathway is also the target of several immunosuppressive drugs used for the treatment of autoimmune disorders, during solid organ and hematopoietic cell transplantations, and as a part of anti-cancer therapy: but what effects these drugs have on neutrophil function, and their broader consequences for immune homeostasis and microbial defense are not yet known. Here, we bring together the emerging literature describing pathology- and drug- induced neutrophil impairment, with particular focus on their effects on calcineurin-NFAT signaling in the innate immune compartment.
Highlights
Neutrophils are the most abundant cells of the innate immune system and play a key role in antimicrobial and antifungal defenses [1]
At the site of infection, pathogens are detected via pattern recognition receptors (PRRs) whose ligation leads to the activation of a complex network of signaling cascades that together orchestrate the neutrophil’s ability to kill microbes via the generation of reactive oxygen species (ROS), degranulation of effector molecules, and the release of neutrophil extracellular traps (NETs) [2, 3]
We will review the latest findings on neutrophils and their functions during calcineurin inhibitors (CNI)-based immunosuppressive therapy and in the immunosuppressive milieu of sepsis, and ask what we can learn from these two situations that might advance our knowledge of neutrophil function/regulation and enable better clinical management of affected patients
Summary
Neutrophils are the most abundant cells of the innate immune system and play a key role in antimicrobial and antifungal defenses [1]. While little direct research has been done into the role of CN-NFAT in driving neutrophil functions or in different neutrophil subsets, studies with patients undergoing immunosuppressive therapy with CNI, or with disease-associated immunosuppression, have generated intriguing insights into this topic.
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