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.

Center for Translational Medicine St Anne's University Hospital Brno Brno Czech Republic

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Alfaadhel T, Cattran D (2015) Management of membranous nephropathy in western countries. Kidney Dis 1: 126–137 PubMed PMC

Aramburu J, Azzoni L, Rao A, Perussia B (1995) Activation and expression of the nuclear factors of activated T cells, NFATp and NFATc, in human natural killer cells: regulation upon CD16 ligand binding. J Exp Med 182: 801–810 PubMed PMC

Bao M, Wang Y, Liu Y, Shi P, Lu H, Sha W, Weng L, Hanabuchi S, Qin J, Plumas J et al (2016) NFATC3 promotes IRF7 transcriptional activity in plasmacytoid dendritic cells. J Exp Med 213: 2383–2398 PubMed PMC

Barbosa CM, Bincoletto C, Barros CC, Ferreira AT, Paredes‐Gamero EJ (2014) PLCgamma2 and PKC are important to myeloid lineage commitment triggered by M‐SCF and G‐CSF. J Cell Biochem 115: 42–51 PubMed

Bhattacharjee A, Majumder S, Das S, Ghosh S, Biswas S, Majumdar S (2016) Leishmania donovani‐induced prostaglandin E2 generation is critically dependent on host toll‐like receptor 2‐cytosolic phospholipase A2 signaling. Infect Immun 84: 2963–2973 PubMed PMC

Bronk CC, Yoder S, Hopewell EL, Yang S, Celis E, Yu XZ, Beg AA (2014) NF‐kappaB is crucial in proximal T‐cell signaling for calcium influx and NFAT activation. Eur J Immunol 44: 3741–3746 PubMed PMC

Busch R, Murti K, Liu J, Patra AK, Muhammad K, Knobeloch KP, Lichtinger M, Bonifer C, Wortge S, Waisman A et al (2016) NFATc1 releases BCL6‐dependent repression of CCR2 agonist expression in peritoneal macrophages from Saccharomyces cerevisiae infected mice. Eur J Immunol 46: 634–646 PubMed

Chiang CY, Veckman V, Limmer K, David M (2012) Phospholipase Cgamma‐2 and intracellular calcium are required for lipopolysaccharide‐induced Toll‐like receptor 4 (TLR4) endocytosis and interferon regulatory factor 3 (IRF3) activation. J Biol Chem 287: 3704–3709 PubMed PMC

Crabtree GR (1989) Contingent genetic regulatory events in T lymphocyte activation. Science 243: 355–361 PubMed

Elloumi HZ, Maharshak N, Rao KN, Kobayashi T, Ryu HS, Muhlbauer M, Li F, Jobin C, Plevy SE (2012) A cell permeable peptide inhibitor of NFAT inhibits macrophage cytokine expression and ameliorates experimental colitis. PLoS ONE 7: e34172 PubMed PMC

Escolano A, Martinez‐Martinez S, Alfranca A, Urso K, Izquierdo HM, Delgado M, Martin F, Sabio G, Sancho D, Gomez‐del Arco P et al (2014) Specific calcineurin targeting in macrophages confers resistance to inflammation via MKP‐1 and p38. EMBO J 33: 1117–1133 PubMed PMC

Fric J, Zelante T, Wong AY, Mertes A, Yu HB, Ricciardi‐Castagnoli P (2012) NFAT control of innate immunity. Blood 120: 1380–1389 PubMed

Fric J, Lim CX, Mertes A, Lee BT, Vigano E, Chen J, Zolezzi F, Poidinger M, Larbi A, Strobl H et al (2014a) Calcium and calcineurin‐NFAT signaling regulate granulocyte‐monocyte progenitor cell cycle via Flt3‐L. Stem Cells 32: 3232–3244 PubMed PMC

Fric J, Zelante T, Ricciardi‐Castagnoli P (2014b) Phagocytosis of particulate antigens – all roads lead to calcineurin/NFAT signaling pathway. Front Immunol 4: 513 PubMed PMC

Goodridge HS, Simmons RM, Underhill DM (2007) Dectin‐1 stimulation by Candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cells. J Immunol 178: 3107–3115 PubMed

Goodridge HS, Reyes CN, Becker CA, Katsumoto TR, Ma J, Wolf AJ, Bose N, Chan AS, Magee AS, Danielson ME et al (2011) Activation of the innate immune receptor Dectin‐1 upon formation of a “phagocytic synapse”. Nature 472: 471–475 PubMed PMC

Granucci F, Vizzardelli C, Pavelka N, Feau S, Persico M, Virzi E, Rescigno M, Moro G, Ricciardi‐Castagnoli P (2001) Inducible IL‐2 production by dendritic cells revealed by global gene expression analysis. Nat Immunol 2: 882–888 PubMed

Granucci F, Feau S, Angeli V, Trottein F, Ricciardi‐Castagnoli P (2003) Early IL‐2 production by mouse dendritic cells is the result of microbial‐induced priming. J Immunol 170: 5075–5081 PubMed

Granucci F, Zanoni I, Pavelka N, Van Dommelen SL, Andoniou CE, Belardelli F, Degli Esposti MA, Ricciardi‐Castagnoli P (2004) A contribution of mouse dendritic cell‐derived IL‐2 for NK cell activation. J Exp Med 200: 287–295 PubMed PMC

Granucci F, Zanoni I, Ricciardi‐Castagnoli P (2006) Natural killer (NK) cell functions can be strongly boosted by activated dendritic cells (DC). Eur J Immunol 36: 2819–2820 PubMed

Greenblatt MB, Aliprantis A, Hu B, Glimcher LH (2010) Calcineurin regulates innate antifungal immunity in neutrophils. J Exp Med 207: 923–931 PubMed PMC

Guiducci C, Valzasina B, Dislich H, Colombo MP (2005) CD40/CD40L interaction regulates CD4+ CD25+ T reg homeostasis through dendritic cell‐produced IL‐2. Eur J Immunol 35: 557–567 PubMed

Herbst S, Shah A, Carby M, Chusney G, Kikkeri N, Dorling A, Bignell E, Shaunak S, Armstrong‐James D (2013) A new and clinically relevant murine model of solid‐organ transplant aspergillosis. Dis Model Mech 6: 643–651 PubMed PMC

Herbst S, Shah A, Mazon Moya M, Marzola V, Jensen B, Reed A, Birrell MA, Saijo S, Mostowy S, Shaunak S et al (2015) Phagocytosis‐dependent activation of a TLR9‐BTK‐calcineurin‐NFAT pathway co‐ordinates innate immunity to Aspergillus fumigatus . EMBO Mol Med 7: 240–258 PubMed PMC

Hilkens CM, Isaacs JD, Thomson AW (2010) Development of dendritic cell‐based immunotherapy for autoimmunity. Int Rev Immunol 29: 156–183 PubMed

Hilkens CM, Isaacs JD (2013) Tolerogenic dendritic cell therapy for rheumatoid arthritis: where are we now? Clin Exp Immunol 172: 148–157 PubMed PMC

Hirai T, Ikeda K, Fujishiro M, Tsushima H, Hayakawa K, Suzuki S, Yamaguchi A, Nozawa K, Morimoto S, Takasaki Y et al (2017) The effectiveness of new triple combination therapy using synthetic disease‐modifying anti‐rheumatic drugs with different pharmacological function against rheumatoid arthritis: the verification by an in vitro and clinical study. Clin Rheumatol 36: 51–58 PubMed

Imbert S, Bresler P, Boissonnas A, Gauthier L, Souchet L, Uzunov M, Leblond V, Mazier D, Nguyen S, Fekkar A (2016) Calcineurin inhibitors impair neutrophil activity against Aspergillus fumigatus in allogeneic hematopoietic stem cell transplant recipients. J Allergy Clin Immunol 138: 860–868 PubMed

Jennings C, Kusler B, Jones PP (2009) Calcineurin inactivation leads to decreased responsiveness to LPS in macrophages and dendritic cells and protects against LPS‐induced toxicity in vivo . Innate immunity 15: 109–120 PubMed PMC

Jin M, Yu B, Zhang W, Zhang W, Xiao Z, Mao Z, Lai Y, Lin D, Ma Q, Pan E et al (2016) Toll‐like receptor 2‐mediated MAPKs and NF‐kappaB activation requires the GNAO1‐dependent pathway in human mast cells. Integr Biol 8: 968–975 PubMed

Kagan JC, Su T, Horng T, Chow A, Akira S, Medzhitov R (2008) TRAM couples endocytosis of Toll‐like receptor 4 to the induction of interferon‐beta. Nat Immunol 9: 361–368 PubMed PMC

Kagan JC (2012) Signaling organelles of the innate immune system. Cell 151: 1168–1178 PubMed PMC

Kang YJ, Kusler B, Otsuka M, Hughes M, Suzuki N, Suzuki S, Yeh WC, Akira S, Han J, Jones PP (2007) Calcineurin negatively regulates TLR‐mediated activation pathways. J Immunol 179: 4598–4607 PubMed

Kayama H, Koga R, Atarashi K, Okuyama M, Kimura T, Mak TW, Uematsu S, Akira S, Takayanagi H, Honda K et al (2009) NFATc1 mediates Toll‐like receptor‐independent innate immune responses during Trypanosoma cruzi infection. PLoS Pathog 5: e1000514 PubMed PMC

Khameneh HJ, Ho AW, Spreafico R, Derks H, Quek HQ, Mortellaro A (2017) The Syk‐NFAT‐IL‐2 pathway in dendritic cells is required for optimal sterile immunity elicited by alum adjuvants. J Immunol 198: 196–204 PubMed PMC

Kim SJ, Chen Z, Chamberlain ND, Essani AB, Volin MV, Amin MA, Volkov S, Gravallese EM, Arami S, Swedler W et al (2014) Ligation of TLR5 promotes myeloid cell infiltration and differentiation into mature osteoclasts in rheumatoid arthritis and experimental arthritis. J Immunol 193: 3902–3913 PubMed PMC

Klein M, Klein‐Hessling S, Palmetshofer A, Serfling E, Tertilt C, Bopp T, Heib V, Becker M, Taube C, Schild H et al (2006) Specific and redundant roles for NFAT transcription factors in the expression of mast cell‐derived cytokines. J Immunol 177: 6667–6674 PubMed

Kraaij T, Bredewold OW, Trompet S, Huizinga TW, Rabelink TJ, de Craen AJ, Teng YK (2016) TAC‐TIC use of tacrolimus‐based regimens in lupus nephritis. Lupus Sci Med 3: e000169 PubMed PMC

Liu ZC, Wang M, Sun WK, Xia D, Tan MM, Ding Y, Qian Q, Su X, Shi Y (2015) Up‐regulation of Dectin‐1 in airway epithelial cells promotes mice defense against invasive pulmonary aspergillosis. Int J Clin Exp Med 8: 17489–17497 PubMed PMC

Ma B, Yu J, Xie C, Sun L, Lin S, Ding J, Luo J, Cai H (2015) Toll‐like receptors promote mitochondrial translocation of nuclear transcription factor nuclear factor of activated T‐cells in prolonged microglial activation. J Neurosci 35: 10799–10814 PubMed PMC

Macian F (2005) NFAT proteins: key regulators of T‐cell development and function. Nat Rev Immunol 5: 472–484 PubMed

Malek TR, Castro I (2010) Interleukin‐2 receptor signaling: at the interface between tolerance and immunity. Immunity 33: 153–165 PubMed PMC

Matsuda S, Moriguchi T, Koyasu S, Nishida E (1998) T lymphocyte activation signals for interleukin‐2 production involve activation of MKK6‐p38 and MKK7‐SAPK/JNK signaling pathways sensitive to cyclosporin A. J Biol Chem 273: 12378–12382 PubMed

Mbongue J, Nicholas D, Firek A, Langridge W (2014) The role of dendritic cells in tissue‐specific autoimmunity. J Immunol Res 2014: 857143 PubMed PMC

Metcalfe S, Alexander D, Turner J (1994) FK506 and cyclosporin A each inhibit antigen‐specific signaling in the T cell line 171 in the absence of a calcium signal. Cell Immunol 158: 46–58 PubMed

Minematsu H, Shin MJ, Celil Aydemir AB, Kim KO, Nizami SA, Chung GJ, Lee FY (2011) Nuclear presence of nuclear factor of activated T cells (NFAT) c3 and c4 is required for Toll‐like receptor‐activated innate inflammatory response of monocytes/macrophages. Cell Signal 23: 1785–1793 PubMed PMC

Miranda MB, Johnson DE (2007) Signal transduction pathways that contribute to myeloid differentiation. Leukemia 21: 1363–1377 PubMed

Miskin JE, Abrams CC, Goatley LC, Dixon LK (1998) A viral mechanism for inhibition of the cellular phosphatase calcineurin. Science 281: 562–565 PubMed

Miskin JE, Abrams CC, Dixon LK (2000) African swine fever virus protein A238L interacts with the cellular phosphatase calcineurin via a binding domain similar to that of NFAT. J Virol 74: 9412–9420 PubMed PMC

Misra DP, Parida JR, Chowdhury AC, Agarwal V (2014) Pulmonary co‐infection with Nocardia and Aspergillus in a patient with adult‐onset Still's disease receiving steroids and tacrolimus. BMJ Case Rep 2014 doi:10.1136/bcr‐2014‐207335 PubMed DOI PMC

Monticelli S, Solymar DC, Rao A (2004) Role of NFAT proteins in IL13 gene transcription in mast cells. J Biol Chem 279: 36210–36218 PubMed

Mourao‐Sa D, Robinson MJ, Zelenay S, Sancho D, Chakravarty P, Larsen R, Plantinga M, Van Rooijen N, Soares MP, Lambrecht B et al (2011) CLEC‐2 signaling via Syk in myeloid cells can regulate inflammatory responses. Eur J Immunol 41: 3040–3053 PubMed

Muller MR, Sasaki Y, Stevanovic I, Lamperti ED, Ghosh S, Sharma S, Gelinas C, Rossi DJ, Pipkin ME, Rajewsky K et al (2009) Requirement for balanced Ca/NFAT signaling in hematopoietic and embryonic development. Proc Natl Acad Sci USA 106: 7034–7039 PubMed PMC

Muller MR, Rao A (2010) NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol 10: 645–656 PubMed

Naniwa T, Iwagaitsu S, Kajiura M (2017) Efficacy of add‐on tacrolimus on methotrexate to maintain clinical remission after rediscontinuation of a tumor necrosis factor inhibitor in rheumatoid arthritis patients who relapsed shortly after discontinuation of the same tumor necrosis factor inhibitor due to clinical remission. Mod Rheumatol 27: 29–34 PubMed

Nicholson LB, Raveney BJ, Munder M (2009) Monocyte dependent regulation of autoimmune inflammation. Curr Mol Med 9: 23–29 PubMed

Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, Anaissie EJ, Brumble LM, Herwaldt L, Ito J et al (2010) Invasive fungal infections among organ transplant recipients: results of the Transplant‐Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis 50: 1101–1111 PubMed

Ranjan R, Deng J, Chung S, Lee YG, Park GY, Xiao L, Joo M, Christman JW, Karpurapu M (2014) The transcription factor nuclear factor of activated T cells c3 modulates the function of macrophages in sepsis. J Innate Immun 6: 754–764 PubMed PMC

Schiff M, Beaulieu A, Scott DL, Rashford M (2010) Mycophenolate mofetil in the treatment of adults with advanced rheumatoid arthritis: three 24‐week, randomized, double‐blind, placebo‐ or cyclosporin‐controlled trials. Clin Drug Invest 30: 613–624 PubMed

Severin S, Pollitt AY, Navarro‐Nunez L, Nash CA, Mourao‐Sa D, Eble JA, Senis YA, Watson SP (2011) Syk‐dependent phosphorylation of CLEC‐2: a novel mechanism of hem‐immunoreceptor tyrosine‐based activation motif signaling. J Biol Chem 286: 4107–4116 PubMed PMC

Shah A, Kannambath S, Herbst S, Rogers A, Soresi S, Carby M, Reed A, Mostowy S, Fisher MC, Shaunak S et al (2016) Calcineurin orchestrates lateral transfer of Aspergillus fumigatus during macrophage cell death. Am J Respir Crit Care Med 194: 1127–1139 PubMed PMC

Shaw JP, Utz PJ, Durand DB, Toole JJ, Emmel EA, Crabtree GR (1988) Identification of a putative regulator of early T cell activation genes. Science 241: 202–205 PubMed

Strijbis K, Tafesse FG, Fairn GD, Witte MD, Dougan SK, Watson N, Spooner E, Esteban A, Vyas VK, Fink GR et al (2013) Bruton's Tyrosine Kinase (BTK) and Vav1 contribute to Dectin1‐dependent phagocytosis of Candida albicans in macrophages. PLoS Pathog 9: e1003446 PubMed PMC

Su B, Jacinto E, Hibi M, Kallunki T, Karin M, Ben‐Neriah Y (1994) JNK is involved in signal integration during costimulation of T lymphocytes. Cell 77: 727–736 PubMed

Tajima K, Amakawa R, Ito T, Miyaji M, Takebayashi M, Fukuhara S (2003) Immunomodulatory effects of cyclosporin A on human peripheral blood dendritic cell subsets. Immunology 108: 321–328 PubMed PMC

Takahashi N, Fujibayashi T, Kida D, Hirano Y, Kato T, Kato D, Saito K, Kaneko A, Yabe Y, Takagi H et al (2015) Concomitant methotrexate and tacrolimus augment the clinical response to abatacept in patients with rheumatoid arthritis with a prior history of biological DMARD use. Rheumatol Int 35: 1707–1716 PubMed

Tassi I, Cella M, Castro I, Gilfillan S, Khan WN, Colonna M (2009) Requirement of phospholipase C‐gamma2 (PLCgamma2) for Dectin‐1‐induced antigen presentation and induction of TH1/TH17 polarization. Eur J Immunol 39: 1369–1378 PubMed

Tourneur E, Ben Mkaddem S, Chassin C, Bens M, Goujon JM, Charles N, Pellefigues C, Aloulou M, Hertig A, Monteiro RC et al (2013) Cyclosporine A impairs nucleotide binding oligomerization domain (Nod1)‐mediated innate antibacterial renal defenses in mice and human transplant recipients. PLoS Pathog 9: e1003152 PubMed PMC

Ulleras E, Karlberg M, Moller Westerberg C, Alfredsson J, Gerondakis S, Strasser A, Nilsson G (2008) NFAT but not NF‐kappaB is critical for transcriptional induction of the prosurvival gene A1 after IgE receptor activation in mast cells. Blood 111: 3081–3089 PubMed PMC

Vandewalle A, Tourneur E, Bens M, Chassin C, Werts C (2014) Calcineurin/NFAT signaling and innate host defence: a role for NOD1‐mediated phagocytic functions. Cell Commun Signal 12: 8 PubMed PMC

Vigano E, Diamond CE, Spreafico R, Balachander A, Sobota RM, Mortellaro A (2015) Human caspase‐4 and caspase‐5 regulate the one‐step non‐canonical inflammasome activation in monocytes. Nat Commun 6: 8761 PubMed PMC

Walczak‐Drzewiecka A, Ratajewski M, Wagner W, Dastych J (2008) HIF‐1alpha is up‐regulated in activated mast cells by a process that involves calcineurin and NFAT. J Immunol 181: 1665–1672 PubMed

Xu S, Huo J, Lee KG, Kurosaki T, Lam KP (2009) Phospholipase Cgamma2 is critical for Dectin‐1‐mediated Ca2+ flux and cytokine production in dendritic cells. J Biol Chem 284: 7038–7046 PubMed PMC

Yamaguchi M, Ando M, Yamamoto R, Akiyama S, Kato S, Katsuno T, Kosugi T, Sato W, Tsuboi N, Yasuda Y et al (2014) Patient age and the prognosis of idiopathic membranous nephropathy. PLoS ONE 9: e110376 PubMed PMC

Yamasaki S, Ishikawa E, Sakuma M, Hara H, Ogata K, Saito T (2008) Mincle is an ITAM‐coupled activating receptor that senses damaged cells. Nat Immunol 9: 1179–1188 PubMed

Yeh H, Markmann JF (2013) Transplantation: are calcineurin inhibitors safer than mTOR inhibitors? Nat Rev Nephrol 9: 11–13 PubMed PMC

Yu HB, Yurieva M, Balachander A, Foo I, Leong X, Zelante T, Zolezzi F, Poidinger M, Ricciardi‐Castagnoli P (2015) NFATc2 mediates epigenetic modification of dendritic cell cytokine and chemokine responses to dectin‐1 stimulation. Nucleic Acids Res 43: 836–847 PubMed PMC

Yuan X, Dee MJ, Altman NH, Malek TR (2015) IL‐2Rbeta‐dependent signaling and CD103 functionally cooperate to maintain tolerance in the gut mucosa. J Immunol 194: 1334–1346 PubMed PMC

Zaidi AK, Thangam ER, Ali H (2006) Distinct roles of Ca2+ mobilization and G protein usage on regulation of Toll‐like receptor function in human and murine mast cells. Immunology 119: 412–420 PubMed PMC

Zanoni I, Ostuni R, Capuano G, Collini M, Caccia M, Ronchi AE, Rocchetti M, Mingozzi F, Foti M, Chirico G et al (2009) CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation. Nature 460: 264–268 PubMed

Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC (2011) CD14 controls the LPS‐induced endocytosis of Toll‐like receptor 4. Cell 147: 868–880 PubMed PMC

Zanoni I, Ostuni R, Barresi S, Di Gioia M, Broggi A, Costa B, Marzi R, Granucci F (2012) CD14 and NFAT mediate lipopolysaccharide‐induced skin edema formation in mice. J Clin Invest 122: 1747–1757 PubMed PMC

Zelante T, Wong AY, Ping TJ, Chen J, Sumatoh HR, Vigano E, Hong Bing Y, Lee B, Zolezzi F, Fric J et al (2015) CD103(+) dendritic cells control Th17 cell function in the lung. Cell Rep 12: 1789–1801 PubMed

Zelante T, Wong AY, Mencarelli A, Foo S, Zolezzi F, Lee B, Poidinger M, Ricciardi‐Castagnoli P, Fric J (2017) Impaired calcineurin signaling in myeloid cells results in downregulation of pentraxin‐3 and increased susceptibility to aspergillosis. Mucosal Immunol 10: 470–480 PubMed

Zhang C, Zhang J, Yang B, Wu C (2008) Cyclosporin A inhibits the production of IL‐17 by memory Th17 cells from healthy individuals and patients with rheumatoid arthritis. Cytokine 42: 345–352 PubMed

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