J Bacteriol Virol.  2016 Mar;46(1):1-12. 10.4167/jbv.2016.46.1.1.

Implications of Calcineurin/NFAT Inhibitors' Regulation of Dendritic Cells and Innate Immune Cells in Islet Xenotransplantation

• Kim YH
• Lee WW
• Park CG

• KMID: 2168737
• DOI: http://doi.org/10.4167/jbv.2016.46.1.1

Abstract

Calcineurin inhibitors, such as cyclosporine and tacrolimus (FK506) are broadly used in organ transplantations as immune suppressants. As the calcineurin/NFAT signaling pathway has been identified as critical pathway in the interleukin-2 (IL-2) production of T cells, inhibition of T-cell derived IL-2 has been considered the major mechanism of calcineurin inhibitors. However, there is increasing evidence that NFAT transcription factor is involved in multiple functions of dendritic cells and innate immune cells as well. NFAT expression is not restricted to T cells, and IL-2 can be produced in dendritic cells and macrophages through the calcineurin/NFAT pathway. Furthermore, it has been discovered that NFAT regulates expressions of several inflammatory mediators, including TNF-α and cyclooxygenase-2 in innate immune cells. Therefore, calcineurin inhibitors may have much broader effects in the transplant recipients than previously being considered. In this review, we reviewed recently discovered roles of NFAT pathway in dendritic cells and innate immune cells, and discussed positive and negative implications of calcineurin inhibitors' broader effects with a focus on islet xenotransplantation.

Keyword

Calcineurin inhibitors; Innate immunity; Islet transplantation; Xenotransplantation

MeSH Terms

Calcineurin
Critical Pathways
Cyclooxygenase 2
Cyclosporine
Dendritic Cells*
Immunity, Innate
Interleukin-2
Islets of Langerhans Transplantation
Macrophages
Organ Transplantation
T-Lymphocytes
Tacrolimus
Transcription Factors
Transplantation
Transplantation, Heterologous*
Transplants
Calcineurin
Cyclooxygenase 2
Cyclosporine
Interleukin-2
Tacrolimus
Transcription Factors

Figure

• 

  Figure 1. The classical calcienruin/NFAT signaling pathway in T cells

• 

  Figure 2. NFAT-mediated IL-2 production in dendritic cells and macrophages

• 

  Figure 3. Instant Blood-Mediated Inflammatory Reaction (IBMIR) and NFAT-mediated targets

Reference

1). Shaw JP, Utz PJ, Durand DB, Toole JJ, Emmel EA, Crabtree GR. Identification of a putative regulator of early T cell activation genes. Science. 1988; 241:202–5.

2). Jain J, McCaffrey PG, Miner Z, Kerppola TK, Lambert JN, Verdine GL, et al. The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature. 1993; 365:352–5.

3). Clipstone NA, Crabtree GR. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature. 1992; 357:695–7.

4). Rao A, Luo C, Hogan PG. Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol. 1997; 15:707–47.

5). Crabtree GR, Olson EN. NFAT signaling: choreographing the social lives of cells. Cell. 2002; 109(Suppl):S67–79.

6). Graef IA, Chen F, Crabtree GR. NFAT signaling in vertebrate development. Curr Opin Genet Dev. 2001; 11:505–12.

7). Hogan PG, Chen L, Nardone J, Rao A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003; 17:2205–32.

8). Macian F. NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol. 2005; 5:472–84.

9). Muller MR, Rao A. NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol. 2010; 10:645–56.

10). Park CG, Bottino R, Hawthorne WJ. Current status of islet xenotransplantation. Int J Surg. 2015; 23:261–6.

11). van der Windt DJ, Bottino R, Kumar G, Wijkstrom M, Hara H, Ezzelarab M, et al. Clinical islet xenotransplantation: how close are we? Diabetes. 2012; 61:3046–55.

12). Ekser B, Ezzelarab M, Hara H, van der Windt DJ, Wijkstrom M, Bottino R, et al. Clinical xenotransplantation: the next medical revolution? Lancet. 2012; 379:672–83.

13). Vadori M, Cozzi E. The immunological barriers to xenotransplantation. Tissue Antigens. 2015; 86:239–53.

14). Goodridge HS, Simmons RM, Underhill DM. Dectin-1 stimulation by Candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cells. J Immunol. 2007; 178:3107–15.

15). Zanoni I, Ostuni R, Capuano G, Collini M, Caccia M, Ronchi AE, et al. CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation. Nature. 2009; 460:264–8.

16). Zanoni I, Bodio C, Broggi A, Ostuni R, Caccia M, Collini M, et al. Similarities and differences of innate immune responses elicited by smooth and rough LPS. Immunol Lett. 2012; 142:41–7.

17). Granucci F, Zanoni I, Pavelka N, Van Dommelen SL, Andoniou CE, Belardelli F, et al. A contribution of mouse dendritic cell-derived IL-2 for NK cell activation. J Exp Med. 2004; 200:287–95.

18). Granucci F, Zanoni I, Ricciardi-Castagnoli P. Natural killer (NK) cell functions can be strongly boosted by activated dendritic cells (DC). Eur J Immunol. 2006; 36:2819–20.

19). Fujii S, Shimizu K, Kronenberg M, Steinman RM. Prolonged IFN-gamma-producing NKT response induced with alpha-galactosylceramide-loaded DCs. Nat Immunol. 2002; 3:867–74.

20). Klein M, Klein-Hessling S, Palmetshofer A, Serfling E, Tertilt C, Bopp T, et al. Specific and redundant roles for NFAT transcription factors in the expression of mast cell-derived cytokines. J Immunol. 2006; 177:6667–74.

21). Aramburu J, Azzoni L, Rao A, Perussia B. 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. 1995; 182:801–10.

22). Christopher MJ, Link DC. Regulation of neutrophil homeostasis. Curr Opin Hematol. 2007; 14:3–8.

23). Hawwari A, Burrows J, Vadas MA, Cockerill PN. The human IL-3 locus is regulated cooperatively by two NFAT-dependent enhancers that have distinct tissue-specific activities. J Immunol. 2002; 169:1876–86.

24). Brettingham-Moore KH, Rao S, Juelich T, Shannon MF, Holloway AF. GM-CSF promoter chromatin remodelling and gene transcription display distinct signal and transcription factor requirements. Nucleic Acids Res. 2005; 33:225–34.

25). Zanoni I, Ostuni R, Barresi S, Di Gioia M, Broggi A, Costa B, et al. CD14 and NFAT mediate lipopolysaccharide-induced skin edema formation in mice. J Clin Invest. 2012; 122:1747–57.

26). Vega A, Chacon P, Monteseirin J, El Bekay R, Alba G, Martin-Nieto J, et al. Expression of the transcription factor NFAT2 in human neutrophils: IgE-dependent, Ca2+- and calcineurin-mediated NFAT2 activation. J Cell Sci. 2007; 120:2328–37.

27). Fric J, Zelante T, Wong AY, Mertes A, Yu HB, Ricciardi-Castagnoli P. NFAT control of innate immunity. Blood. 2012; 120:1380–9.

28). Ulleras E, Karlberg M, Moller Westerberg C, Alfredsson J, Gerondakis S, Strasser A, et al. NFAT but not NF-kappaB is critical for transcriptional induction of the prosurvival gene A1 after IgE receptor activation in mast cells. Blood. 2008; 111:3081–9.

29). Xiang Z, Ahmed AA, Moller C, Nakayama K, Hatakeyama S, Nilsson G. Essential role of the prosurvival bcl-2 homologue A1 in mast cell survival after allergic activation. J Exp Med. 2001; 194:1561–9.

30). Orlofsky A, Somogyi RD, Weiss LM, Prystowsky MB. The murine antiapoptotic protein A1 is induced in inflammatory macrophages and constitutively expressed in neutrophils. J Immunol. 1999; 163:412–9.

31). Hamasaki A, Sendo F, Nakayama K, Ishida N, Negishi I, Nakayama K, et al. Accelerated neutrophil apoptosis in mice lacking A1-a, a subtype of the bcl-2-related A1 gene. J Exp Med. 1998; 188:1985–92.

32). Lin EY, Orlofsky A, Wang HG, Reed JC, Prystowsky MB. A1, a Bcl-2 family member, prolongs cell survival and permits myeloid differentiation. Blood. 1996; 87:983–92.

33). Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000; 343:230–8.

34). Bellin MD, Barton FB, Heitman A, Harmon JV, Kandaswamy R, Balamurugan AN, et al. Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant. 2012; 12:1576–83.

35). Qi M, Kinzer K, Danielson KK, Martellotto J, Barbaro B, Wang Y, et al. Five-year follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience. Acta Diabetol. 2014; 51:833–43.

36). Rickels MR, Liu C, Shlansky-Goldberg RD, Soleimanpour SA, Vivek K, Kamoun M, et al. Improvement in beta-cell secretory capacity after human islet transplantation according to the CIT07 protocol. Diabetes. 2013; 62:2890–7.

37). Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999; 340:253–9.

38). Zalevsky J, Secher T, Ezhevsky SA, Janot L, Steed PM, O'Brien C, et al. Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection. J Immunol. 2007; 179:1872–83.

39). Cardona K, Korbutt GS, Milas Z, Lyon J, Cano J, Jiang W, et al. Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med. 2006; 12:304–6.

40). Cardona K, Milas Z, Strobert E, Cano J, Jiang W, Safley SA, et al. Engraftment of adult porcine islet xenografts in diabetic nonhuman primates through targeting of costimulation pathways. Am J Transplant. 2007; 7:2260–8.

41). Thompson P, Badell IR, Lowe M, Cano J, Song M, Leopardi F, et al. Islet xenotransplantation using gal-deficient neonatal donors improves engraftment and function. Am J Transplant. 2011; 11:2593–602.

42). Thompson P, Badell IR, Lowe M, Turner A, Cano J, Avila J, et al. Alternative immunomodulatory strategies for xenotransplantation: CD40/154 pathway-sparing regimens promote xenograft survival. Am J Transplant. 2012; 12:1765–75.

43). Thompson P, Cardona K, Russell M, Badell IR, Shaffer V, Korbutt G, et al. CD40-specific costimulation blockade enhances neonatal porcine islet survival in non-human primates. Am J Transplant. 2011; 11:947–57.

44). Shin JS, Kim JM, Kim JS, Min BH, Kim YH, Kim HJ, et al. Long-Term Control of Diabetes in Immunosuppressed Nonhuman Primates (NHP) by the Transplantation of Adult Porcine Islets. Am J Transplant. 2015; 15:2837–50.

45). Jung KC, Park CG, Jeon YK, Park HJ, Ban YL, Min HS, et al. In situ induction of dendritic cell-based T cell tolerance in humanized mice and nonhuman primates. J Exp Med. 2011; 208:2477–88.

46). Bennet W, Groth CG, Larsson R, Nilsson B, Korsgren O. Isolated human islets trigger an instant blood mediated inflammatory reaction: implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes. Ups J Med Sci. 2000; 105:125–33.

47). Nilsson B, Ekdahl KN, Korsgren O. Control of instant blood-mediated inflammatory reaction to improve islets of Langerhans engraftment. Curr Opin Organ Transplant. 2011; 16:620–6.

48). Moberg L, Johansson H, Lukinius A, Berne C, Foss A, Källen R, et al. Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. The Lancet. 2002; 360:2039–45.

49). Vanichakarn P, Blair P, Wu C, Freedman JE, Chakrabarti S. Neutrophil CD40 enhances platelet-mediated inflammation. Thromb Res. 2008; 122:346–58.

50). Crist SA, Sprague DL, Ratliff TL. Nuclear factor of activated T cells (NFAT) mediates CD154 expression in megakaryocytes. Blood. 2008; 111:3553–61.

51). Crist SA, Elzey BD, Ahmann MT, Ratliff TL. Early growth response-1 (EGR-1) and nuclear factor of activated T cells (NFAT) cooperate to mediate CD40L expression in megakaryocytes and platelets. J Biol Chem. 2013; 288:33985–96.

52). Armesilla AL, Lorenzo E, Gomez del Arco P, Martinez-Martinez S, Alfranca A, Redondo JM. Vascular endothelial growth factor activates nuclear factor of activated T cells in human endothelial cells: a role for tissue factor gene expression. Mol Cell Biol. 1999; 19:2032–43.

53). Johansson H, Lukinius A, Moberg L, Lundgren T, Berne C, Foss A, et al. Tissue factor produced by the endocrine cells of the islets of Langerhans is associated with a negative outcome of clinical islet transplantation. Diabetes. 2005; 54:1755–62.

54). Billing H, Breil T, Schmidt J, Tonshoff B, Schmitt CP, Giese T, et al. Pharmacodynamic monitoring by residual NFAT-regulated gene expression in stable pediatric liver transplant recipients. Pediatr Transplant. 2012; 16:187–94.

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

56). Greenblatt MB, Aliprantis A, Hu B, Glimcher LH. Calcineurin regulates innate antifungal immunity in neutrophils. J Exp Med. 2010; 207:923–31.

57). Tourneur E, Ben Mkaddem S, Chassin C, Bens M, Goujon JM, Charles N, et al. Cyclosporine A Impairs Nucleotide Binding Oligomerization Domain (Nod1)-Mediated Innate Antibacterial Renal Defenses in Mice and Human Transplant Recipients. Plos Pathogens. 2013; 9.

58). Berland R, Wortis HH. Normal B-1a cell development requires B cell-intrinsic NFATc1 activity. Proc Natl Acad Sci U S A. 2003; 100:13459–64.

59). Neilson JR, Winslow MM, Hur EM, Crabtree GR. Calcineurin B1 is essential for positive but not negative selection during thymocyte development. Immunity. 2004; 20:255–66.

60). Winslow MM, Gallo EM, Neilson JR, Crabtree GR. The calcineurin phosphatase complex modulates immunogenic B cell responses. Immunity. 2006; 24:141–52.

61). Muller MR, Sasaki Y, Stevanovic I, Lamperti ED, Ghosh S, Sharma S, et al. Requirement for balanced Ca/NFAT signaling in hematopoietic and embryonic development. Proc Natl Acad Sci U S A. 2009; 106:7034–9.

62). Kiani A, Habermann I, Haase M, Feldmann S, Boxberger S, Sanchez-Fernandez MA, et al. Expression and regulation of NFAT (nuclear factors of activated T cells) in human CD34+ cells: down-regulation upon myeloid differentiation. J Leukoc Biol. 2004; 76:1057–65.

63). Kiani A, Kuithan H, Kuithan F, Kyttala S, Habermann I, Temme A, et al. Expression analysis of nuclear factor of activated T cells (NFAT) during myeloid differentiation of CD34+ cells: regulation of Fas ligand gene expression in megakaryocytes. Exp Hematol. 2007; 35:757–70.

64). Fric J, Lim CX, Koh EG, Hofmann B, Chen J, Tay HS, et al. Calcineurin/NFAT signalling inhibits myeloid haematopoiesis. EMBO Mol Med. 2012; 4:269–82.

65). Mourao-Sa D, Robinson MJ, Zelenay S, Sancho D, Chakravarty P, Larsen R, et al. CLEC-2 signaling via Syk in myeloid cells can regulate inflammatory responses. Eur J Immunol. 2011; 41:3040–53.

66). Walsh PT, Taylor DK, Turka LA. Tregs and transplantation tolerance. J Clin Invest. 2004; 114:1398–403.

67). Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol. 2004; 4:665–74.

68). Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic maintenance of natural Foxp3 (+) CD25 (+) CD4 (+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med. 2005; 201:723–35.

69). Guiducci C, Valzasina B, Dislich H, Colombo MP. CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell-produced IL-2. Eur J Immunol. 2005; 35:557–67.

70). Bopp T, Palmetshofer A, Serfling E, Heib V, Schmitt S, Richter C, et al. NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells. J Exp Med. 2005; 201:181–7.

71). Hu H, Djuretic I, Sundrud MS, Rao A. Transcriptional partners in regulatory T cells: Foxp3, Runx and NFAT. Trends Immunol. 2007; 28:329–32.

72). Sumpter TL, Payne KK, Wilkes DS. Regulation of the NFAT pathway discriminates CD4+CD25+ regulatory T cells from CD4+CD25- helper T cells. J Leukoc Biol. 2008; 83:708–17.

73). Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, Stroud JC, et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell. 2006; 126:375–87.

74). Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature. 2010; 463:808–12.

75). Tone Y, Furuuchi K, Kojima Y, Tykocinski ML, Greene MI, Tone M. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat Immunol. 2008; 9:194–202.

76). Walczak-Drzewiecka A, Ratajewski M, Wagner W, Dastych J. HIF-1alpha is up-regulated in activated mast cells by a process that involves calcineurin and NFAT. J Immunol. 2008; 181:1665–72.

77). Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol (1985). 2000; 88:1474–80.

78). Hernandez GL, Volpert OV, Iniguez MA, Lorenzo E, Martinez-Martinez S, Grau R, et al. Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2. J Exp Med. 2001; 193:607–20.

79). Jinnin M, Medici D, Park L, Limaye N, Liu Y, Boscolo E, et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med. 2008; 14:1236–46.

80). Soleimanpour SA, Crutchlow MF, Ferrari AM, Raum JC, Groff DN, Rankin MM, et al. Calcineurin signaling regulates human islet {beta}-cell survival. J Biol Chem. 2010; 285:40050–9.

81). Ozbay LA, Smidt K, Mortensen DM, Carstens J, Jorgensen KA, Rungby J. Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells. Br J Pharmacol. 2011; 162:136–46.

82). Lawrence MC, Bhatt HS, Easom RA. NFAT regulates insulin gene promoter activity in response to synergistic pathways induced by glucose and glucagon-like peptide-1. Diabetes. 2002; 51:691–8.

83). DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988; 37:667–87.

84). Calabria E, Ciciliot S, Moretti I, Garcia M, Picard A, Dyar KA, et al. NFAT isoforms control activity-dependent muscle fiber type specification. Proc Natl Acad Sci U S A. 2009; 106:13335–40.

85). Rana ZA, Gundersen K, Buonanno A. Activity-dependent repression of muscle genes by NFAT. Proc Natl Acad Sci U S A. 2008; 105:5921–6.

86). McCullagh KJ, Calabria E, Pallafacchina G, Ciciliot S, Serrano AL, Argentini C, et al. NFAT is a nerve activity sensor in skeletal muscle and controls activity-dependent myosin switching. Proc Natl Acad Sci U S A. 2004; 101:10590–5.

87). Chakkera HA, Mandarino LJ. Calcineurin inhibition and new-onset diabetes mellitus after transplantation. Transplantation. 2013; 95:647–52.

88). Cosio FG, Kudva Y, van der Velde M, Larson TS, Textor SC, Griffin MD, et al. New onset hyperglycemia and diabetes are associated with increased cardiovascular risk after kidney transplantation. Kidney Int. 2005; 67:2415–21.

89). Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant. 2003; 3:178–85.

90). Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant. 2004; 4:583–95.

91). Drachenberg CB, Klassen DK, Weir MR, Wiland A, Fink JC, Bartlett ST, et al. Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Transplantation. 1999; 68:396–402.

92). Oetjen E, Baun D, Beimesche S, Krause D, Cierny I, Blume R, et al. Inhibition of human insulin gene transcription by the immunosuppressive drugs cyclosporin A and tacrolimus in primary, mature islets of transgenic mice. Mol Pharmacol. 2003; 63:1289–95.

93). Hjelmesaeth J, Hagen LT, Asberg A, Midtvedt K, Storset O, Halvorsen CE, et al. The impact of short-term ciclosporin A treatment on insulin secretion and insulin sensitivity in man. Nephrol Dial Transplant. 2007; 22:1743–9.

94). Kutkuhn B, Hollenbeck M, Heering P, Koch M, Voiculescu A, Reinhard T, et al. Development of insulin resistance and elevated blood pressure during therapy with cyclosporine A. Blood Press. 1997; 6:13–7.

95). Wahlstrom HE, Akimoto R, Endres D, Kolterman O, Moossa AR. Recovery and hypersecretion of insulin and reversal of insulin resistance after withdrawal of short-term cyclosporine treatment. Transplantation. 1992; 53:1190–5.