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Review
. 2020 Mar 10:11:195.
doi: 10.3389/fimmu.2020.00195. eCollection 2020.

The Role of Calcium-Calcineurin-NFAT Signaling Pathway in Health and Autoimmune Diseases

Yune-Jung Park  1   2 , Seung-Ah Yoo  1   3 , Mingyo Kim  4 , Wan-Uk Kim  1   3   5
Affiliations
Review

The Role of Calcium-Calcineurin-NFAT Signaling Pathway in Health and Autoimmune Diseases

Yune-Jung Park et al. Front Immunol. .

Abstract

Calcium (Ca2+) is an essential signaling molecule that controls a wide range of biological functions. In the immune system, calcium signals play a central role in a variety of cellular functions such as proliferation, differentiation, apoptosis, and numerous gene transcriptions. During an immune response, the engagement of T-cell and B-cell antigen receptors induces a decrease in the intracellular Ca2+ store and then activates store-operated Ca2+ entry (SOCE) to raise the intracellular Ca2+ concentration, which is mediated by the Ca2+ release-activated Ca2+ (CRAC) channels. Recently, identification of the two critical regulators of the CRAC channel, stromal interaction molecule (STIM) and Orai1, has broadened our understanding of the regulatory mechanisms of Ca2+ signaling in lymphocytes. Repetitive or prolonged increase in intracellular Ca2+ is required for the calcineurin-mediated dephosphorylation of the nuclear factor of an activated T cell (NFAT). Recent data indicate that Ca2+-calcineurin-NFAT1 to 4 pathways are dysregulated in autoimmune diseases. Therefore, calcineurin inhibitors, cyclosporine and tacrolimus, have been used for the treatment of such autoimmune diseases as systemic lupus erythematosus and rheumatoid arthritis. Here, we review the role of the Ca2+-calcineurin-NFAT signaling pathway in health and diseases, focusing on the STIM and Orai1, and discuss the deregulated calcium-mediated calcineurin-NFAT pathway in autoimmune diseases.

Keywords: Ca2+ signaling; autoimmune disease; calcineurin; calcium; nuclear factor of an activated T-cell.

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Figures

Figure 1
Figure 1
Schematic of calcium (Ca2+) regulation in a cell. Ca2+ entry is controlled by receptor-mediated Ca2+ (ROC) entry, transient receptor potential (TRP) channels, voltage-gated Ca2+ channels (VOCC), and Ca2+ release-activated Ca2+ (CRAC) activated by the STIM1 protein. Ca2+ efflux is mediated by plasma membrane (PM) Ca2+ ATPase (PMCA), Na+/Ca2+ exchanger (NCX), or Na+/Ca2+/K+ exchanger (NCKX). When the Ca2+-mobilizing agonist (e.g., receptor engagement by antigen) binds to ROC, it results in the activation of phospholipase C (PLC). PLC cleaves the phosphatidylinositol-4,5-bisphosphate (PIP2) to generate the following second messengers, inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 binds to IP3 receptors (IP3Rs) located on the surface of the endoplasmic reticulum (ER) and activates the release of Ca2+. The release of Ca2+ from the ER and sarcoplasmic reticulum (SR) occurs through IP3R. When ER Ca2+ stores are depleted, STIM1 aggregates to the ER–PM junction. STIM1 recruits the Orai1, and then the CRAC channel is activated. Influx of Ca2+ via Orai1 induces the recruitment of TRPC1 from vesicles into the PM. SMOCs, second messenger-operated channels; GP, G proteins.
Figure 2
Figure 2
Potential role of calcium (Ca2+)–calcineurin–nuclear factor of an activated T cell (NFAT) pathway in innate and adaptive immune cells involving rheumatoid arthritis (RA) pathogenesis. RA is characterized by infiltration of various inflammatory cells such as macrophages, T cells, and B cells, in addition to hyperactivation and proliferation of fibroblast-like synoviocytes (FLSs). Pro-inflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), can induce an increase in intracellular Ca2+ concentration. Subsequently, activated calcineurin propagates a wide range of signals essential to the hyperactivation of diverse immune cells involving RA pathogenesis. In T cells, activated calcineurin promotes NFAT and nuclear factor κB (NF-κB) and decisively controls T cell function, growth, and apoptosis. The calcineurin–NFAT axis can also upegulate CD154 transcription, thereby inducing B cell differentiation and antibody production. Beyond its role in lymphocytes, Ca2+-calcineurin–NFAT seems to directly activate innate and matrix metalloproteinases. Calcineurin–NFAT signaling mediates vascular endothelial growth factor (VEGF)-induced endothelial migration and proliferation and thereby can enhance pathologic angiogenesis in RA synovia (88, 89). Additionally, the receptor activator of nuclear factor-κB ligand (RANKL)-induced increase in intracellular Ca2+ levels triggers the Ca2+-calcineurin pathway in osteoclasts, which promotes osteoclastogenesis through NFATc1 activation. Taken together, dysregulated intracellular Ca2+ store and Ca2+ response contribute to the pathogenesis of RA by activating calcineurin–NFAT pathway in multiple types of cells.
Figure 3
Figure 3
Calcium (Ca2+)–calcineurin–nuclear factor of an activated T cell (NFAT) signaling pathway as a novel therapeutic target. Orai1 is a plasma membrane protein with four transmembrane segments. Stromal interaction molecule 1 (STIM1) is a single-pass transmembrane protein located in the endoplasmic reticulum (ER). The increase in intracellular Ca2+ concentration by Ca2+ entry through Ca2+ release-activated Ca2+ (CRAC)/Orai1 induces the phosphatase calcineurin. As a result, the activated calcineurin dephosphorylates several serine residues of the NFAT. The NFAT then translocates to the nucleus where it binds to DNA and regulates target gene expression. Some ions or small molecules, including La3+, SKF96365, and 2-ABP, are able to inhibit the CRAC channel. Again, already-commercialized cyclosporine A and tacrolimus inhibit calcineurin. Since dysregulated Ca2+ signaling is involved in the pathogenesis of autoimmune diseases, intervention of Ca2+ signaling in store-operated Ca2+ entry (SOCE) through the Orai1–STIM1 pathway may be a promising approach to control autoimmune diseases.
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