Essential Roles of Transcription Factor NFAT in Health and Autoimmune Inflammatory Diseases

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Background

As seen through the success of JAK3 inhibitors in the treatment of rheumatoid arthritis (RA), a representative autoimmune disease, the identification and therapeutic targeting of key signalling pathways regulating distinct sets of genes remains an important issue in the post-genome era. Nuclear factor of activated T‐cell (NFAT) is one of the key transcription factors regulating innate immunity as well as adaptive immunity, and its dysfunction has been implicated in the pathogenesis of a variety of autoimmune diseases, including RA. The NFAT family consists of NFAT1 to 4 and NFAT5. NFAT1 to 4, but not NFAT5, are all activated by calcineurin and have a conserved N-terminal domain containing calcineurin docking sites. Defects in intracellular calcium homeostasis have been identified in the lymphocytes and synoviocytes of RA patients, which may be associated with deregulated calcineurin–NFAT1 to 4 signalling in RA. Thus, the calcineurin inhibitors, Cyclosporine and Tacrolimus, have been successfully used for RA treatment and are now being tested for efficacy in a diverse range of other autoimmune pathologies. Interestingly, NFAT5, an osmo-sensitive transcription factor independent of calcineurin, is also activated in synovial tissues and in cells derived from RA patients. Recent data indicate that high salt-induced NFAT5 expression is crucial for Th17 cell generation, contributing to the development of autoimmunity. NFAT5 also confers rheumatoid macrophages and synoviocytes apoptotic resistance under isotonic conditions and promotes chronic arthritis in mice, suggesting that it may be a new therapeutic target for RA.

In this Research Topic, we aim to discuss NFAT1 to 4 and NFAT5 control of rheumatoid inflammation and other autoimmune diseases in the context of recent therapeutic developments. We welcome the submission of articles covering the following topics:

1. Overview of NFAT1 to 4 and NFAT5 including:
1.1. Gene, protein, molecular structure of NFAT1 to 4 and NFAT5.
1.2. Expression and regulation of NFAT1 to 4 and NFAT5 in different tissues.
1.3. Biologic functions of NFAT1 to 4 and NFAT5.

2. The role of calcium-mediated signaling in the pathogenesis of autoimmune and inflammatory diseases including:
2.1. Essential role of NFAT1 to 4 in the activation of lymphocytes, myeloid cells and osteoclasts.
2.2. Role of NFAT1 to 4 in health and diseases.
2.3. Deregulation of calcium, calcineurin, and NFAT1 to 4 pathways in RA and other autoimmune diseases.

3. Regulation of Calcineurin-NFAT1 to 4 signaling for treatment for autoimmune diseases:
3.1. Deregulation of calcium, calcineurin, and NFAT1 to 4 pathways in RA pathogenesis.
3.2. Mode of action, efficacy, and safety of Cyclosporine A and Tacrolimus for active RA.
3.3. Revisit to calcineurin inhibitors with therapeutic advancement in autoimmune diseases; 3.4. Drug repurposing for the treatment of lupus, autoimmune nephropathy, and Sjögren's syndrome.

4. Role of NFAT5 in the immune system and pathogenesis of autoimmune and inflammatory diseases:
4.1. High salt and Th17 polarity.
4.2. High salt regulation of innate immunity.
4.3. Role of NFAT5 for cartilage integrity.
4.4. Tonicity-independent role of NFAT5 in innate immunity, including macrophage activation and survival.
4.5. Requirement of NFAT5 for the progression of chronic arthritis.

Keywords: NFAT, Rheumatoid arthritis, Autoimmunity

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