Abstract
Myeloid leucocytes mediate host protection against infection and critically regulate inflammatory responses in body tissues. Pattern recognition receptor signalling is crucial for myeloid cell responses to pathogens, but growing evidence suggests an equally potent role for Calcineurin–NFAT signalling in control of myeloid cell function. All major subsets of myeloid leucocytes employ Calcineurin–NFAT signalling during immune responses to pathogens and/or tissue damage, but the influence this pathway exerts on pathogen clearance and host susceptibility to infection is not fully understood. Recent data from experimental models indicate that Calcineurin‐NFAT signalling is essential for infection control, and calcineurin inhibitors used in transplantation medicine (including cyclosporine A and tacrolimus) are now being tested for efficacy in a diverse range of inflammatory conditions and autoimmune pathologies. Efforts to repurpose calcineurin inhibitor drugs for new therapeutic applications may yield rapid improvements in clinical outcomes, but the potential impact of these compounds on myeloid cell function in treated patients is largely unknown. Here we discuss Calcineurin–NFAT control of myeloid leucocyte function in the context of recent therapeutic developments and ongoing clinical studies.
Highlights
During an adaptive immune response, engagement of the T-cell receptor stimulates an increase in intracellular calcium that promotes calmodulin binding to the serine/threonine protein phosphatase enzyme calcineurin
The Calcineurin–nuclear factor of activated T-cell (NFAT) pathway was initially described in T cells, where NFAT acts as a master regulator of lymphocyte development, expression of interleukin (IL)-2, and controls major effector T-cell functions
A role for calcium-NFAT signalling in innate immunity was initially identified in NK cells (Aramburu et al, 1995), and later reported in macrophages and dendritic cells (DCs) stimulated through Dectin-1 using either Candida albicans or zymosan, which modulated expression of key transcription factors (Egr2, Egr3) and pro-inflammatory mediators including Cox-2, IL-2, IL-10 and IL-12p70 (Goodridge et al, 2007; Xu et al, 2009)
Summary
During an adaptive immune response, engagement of the T-cell receptor stimulates an increase in intracellular calcium that promotes calmodulin binding to the serine/threonine protein phosphatase enzyme calcineurin. Given that NFAT can cooperate with transcription factors such as AP-1 and NF-kB to modify immune responses (Crabtree, 1989), it is perhaps not surprising that calcineurin inhibitors are thought to mediate wide-ranging effects that can impact on myeloid cell function. There are only limited data available from studies of human tissues and patient samples to support a role for NFAT in myeloid cell responses to major pathogens in vivo.
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