Calcineurin-NFAT signalling in myeloid leucocytes: new prospects and pitfalls in immunosuppressive therapy

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.

Keywords: Dectin‐1; TLR4; cyclosporine A; immunosuppression; tacrolimus.

Figure 1. PRR signal integration with the Calcineurin–NFAT pathway

Multiple different pattern recognition receptors (PRRs) have been reported to trigger Calcineurin–NFAT signalling upon ligand binding. In particular, TLRs and C‐type lectin receptors (CLR) play critical roles in NFAT activation during innate immune responses. The observation that LPS exposure can stimulate NFAT‐mediated IL‐2 expression focused the majority of early research on the role of TLR4 (Granucci et al, 2001, 2003). The LPS co‐receptor CD14 was later also reported to promote Calcineurin–NFAT activation via recruitment of Syk (Zanoni et al, 2009). In mast cells, heterodimers of TLR1‐TLR2 recognize Pam₃ CSK ₄ and drive the recruitment of Fc‐γ receptor which contains ITAM motifs (Jin et al, 2016). TLR9 can also promote NFAT activation upon exposure to Aspergillus fumigatus conidia in acidified endosomes, which results in recruitment of BTK, activation of PLCγ followed by increase in intracellular calcium concentration and NFAT translocation to the nucleus (Herbst et al, 2015). Alternatively, Syk recruitment, PLCγ activation and nuclear localization of NFAT can instead be induced by ligand binding of ITAM‐containing CLRs such as Dectin‐1 (Goodridge et al, 2007), macrophage‐inducible Ca²⁺‐dependent lectin (Mincle) (Yamasaki et al, 2008) and CLEC‐2 (Mourao‐Sa et al, 2011; Severin et al, 2011).

Figure 2. Clinical testing of calcineurin inhibitors cyclosporine A and tacrolimus in autoimmune disorders

(A) Increasing number of clinical studies testing “off‐label” calcineurin inhibitor use for the treatment of autoimmune disorders. Histograms show studies of tacrolimus and cyclosporine A as well as the year each study was completed or last updated (clinicaltrials.gov). (B) Graphical overview of the major autoimmune disorders targeted using calcineurin inhibitors.