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The immunobiology of MIF: function, genetics and prospects for precision medicine

Nature Reviews Rheumatology volume 15, pages 427–437 (2019)Cite this article

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Abstract

The role of macrophage migration inhibitory factor (MIF) in autoimmunity is underscored by data showing that common functional polymorphisms in MIF are associated with disease susceptibility or clinical severity. MIF can regulate glucocorticoid-mediated immunosuppression and has a prominent function in cell survival signalling. Further specific functions of MIF are now being defined in different autoimmune diseases and MIF-targeted biologic therapeutics are in early-stage clinical trials. The unique structure of MIF is also directing the development of small-molecule MIF antagonists. Together, these efforts could provide a means of selectively intervening in pathogenesis and overcoming MIF-related genetic susceptibility to many rheumatic diseases.

Key points

  • Functional MIF polymorphisms are associated with autoimmune and rheumatic disease susceptibility and severity.

  • MIF regulation of glucocorticoid immunosuppression and a prominent function in cell survival signalling place MIF in a unique position in the host response.

  • Biologic and small-molecule therapies targeting MIF are in clinical evaluation.

  • Structural features of MIF make this cytokine suitable for small-molecule antagonism in rheumatic diseases.

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Fig. 1: Structure of two MIF cytokine superfamily members.
Fig. 2: MIF expression and signalling.
Fig. 3: The MIF–CD74–CD44 signal transduction cascade mediates activation and survival signalling in B cells.
Fig. 4: Diagram of the human MIF gene showing its exonic structure and the variant microsatellites in the promoter region.

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References

  1. Zhong, X. B. et al. Simultaneous detection of microsatellite repeats and SNPs in the macrophage migration inhibitory factor (MIF) gene by thin-film biosensor chips and application to rural field studies. Nucleic Acids Res. 33, 121–129 (2005).

    Google Scholar 

  2. Yende, S. et al. The influence of MIF polymorphisms on outcome from community-acquired pneumonia. FASEB J. 23, 2403–2411 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Renner, P. et al. A functional microsatellite of the macrophage migration inhibitory factor gene associated with meningococcal disease. FASEB J. 26, 907–916 (2012).

    CAS  PubMed  Google Scholar 

  4. Awandare, G. A. et al. MIF promoter polymorphisms and susceptibility to severe malarial anemia. J. Infect. Dis. 15, 629–637 (2009).

    Google Scholar 

  5. Das, R. et al. Macrophage migration inhibitory factor (MIF) is a critical mediator of the innate immune response to Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 110, E2997–E3006 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Plant, B. J. et al. Cystic fibrosis, disease severity and a macrophage migration inhibitory factor polymorphism. Am. J. Respir. Crit. Care Med. 172, 1412–1415 (2005).

    PubMed  Google Scholar 

  7. de Jesus Fernandes Covas, C. et al. Candidate gene case-control and functional study shows macrophage inhibitory factor (MIF) polymorphism is associated with cutaneous leishmaniasis. Cytokine 61, 168–172 (2013).

    PubMed  Google Scholar 

  8. Torres, O. A. et al. Association of the macrophage migration inhibitory factor -173G/C polymorphism with Chagas disease. Hum. Immunol. 70, 543–546 (2009).

    CAS  PubMed  Google Scholar 

  9. Savva, A. et al. Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis. Proc. Natl Acad. Sci. USA 113, 3597–3602 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Das, R. et al. Association between high expression macrophage migration inhibitory factor (MIF) alleles and West Nile virus encephalitis. Cytokine 78, 51–54 (2016).

    CAS  PubMed  Google Scholar 

  11. Das, R. et al. Functional macrophage migration inhibitory factor (MIF) polymorphisms are associated with Gram-negative bacteremia in older adults. J. Infect. Dis. 209, 764–768 (2013).

    PubMed  PubMed Central  Google Scholar 

  12. Baugh, J. A. et al. A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis. Genes Immun. 3, 170–176 (2002).

    CAS  PubMed  Google Scholar 

  13. Radstake, T. R. D. J. et al. Correlation of rheumatoid arthritis severity with the genetic functional variants and circulating levels of macrophage migration inhibitory factor. Arthritis Rheum. 52, 3020–3029 (2005).

    CAS  PubMed  Google Scholar 

  14. Llamas-Covarrubias, M. A. et al. Macrophage migration inhibitory factor (MIF): genetic evidence for participation in early onset and early stage rheumatoid arthritis. Cytokine 61, 759–765 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Donn, R. et al. A functional promoter haplotype of macrophage migration inhibitory factor is linked and associated with juvenile idiopathic arthritis. Arthritis Rheum. 50, 1604–1610 (2004).

    PubMed  Google Scholar 

  16. Donn, R. et al. Mutation screening of the macrophage migration inhibitory factor gene: positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis. Arthritis Rheum. 46, 2402–2409 (2002).

    CAS  PubMed  Google Scholar 

  17. Wu, S. P. et al. MIF promoter polymorphisms influence the clinical expression of scleroderma. Arthritis Rheum. 54, 3661–3669 (2006).

    CAS  PubMed  Google Scholar 

  18. Bossini-Castillo, L. et al. Confirmation of association of the macrophage migration inhibitory factor gene with systemic sclerosis in a large European population. Rheumatology 50, 1976–1981 (2011).

    CAS  PubMed  Google Scholar 

  19. Sanchez, E. et al. Evidence of association of macrophage migration inhibitory factor gene polymorphisms with systemic lupus erythematosus. Genes Immun. 7, 433–436 (2006).

    CAS  PubMed  Google Scholar 

  20. Sreih, A. G. et al. Dual effect of MIF gene on the development and the severity of human systemic lupus erythematosus. Arthritis Rheum. 63, 3942–3951 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. De la Cruz-Mosso, U. et al. Macrophage migration inhibitory factor: association of -794 CATT5-8 and -173 G > C polymorphisms with TNF-α in systemic lupus erythematosus. Hum. Immunol. 75, 433–439 (2014).

    PubMed  PubMed Central  Google Scholar 

  22. Sreih, A. G. et al. Role of macrophage migration inhibitory factor in granulomatosis with polyangiitis. Arthritis Rheumatol. 70, 2077–2086 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Sparkes, A. et al. The non-mammalian MIF superfamily. Immunobiology 222, 473–482 (2017).

    CAS  PubMed  Google Scholar 

  24. Rich, A. R. & Lewis, M. R. The nature of allergy in tuberculosis as revealed by tissue culture studies. Bull. Johns Hopkins Hosp. 50, 115–131 (1932).

    Google Scholar 

  25. George, M. & Vaughn, J. H. In vitro cell migration as a model for delayed hypersensitivity. Proc. Soc. Exp. Biol. Med. 111, 514–521 (1962).

    CAS  PubMed  Google Scholar 

  26. David, J. Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc. Natl Acad. Sci. USA 56, 72–77 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Bernhagen, J. et al. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365, 756–759 (1993).

    CAS  PubMed  Google Scholar 

  28. Bernhagen, J. et al. Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration inhibitory factor (MIF). Biochemistry 33, 14144–14155 (1994).

    CAS  PubMed  Google Scholar 

  29. [No authors listed]. Retraction: human recombinant migration inhibitory factor activates human macrophages to kill Leishmania donovani. J. Immunol. 189, 3261 (2012).

  30. Suzuki, M. et al. Crystal structure of the macrophage migration inhibitory factor from rat liver. Nat. Struct. Biol. 3, 259–266 (1996).

    CAS  PubMed  Google Scholar 

  31. Sun, H. W., Bernhagen, J., Bucala, R. & Lolis, E. Crystal structure at 2.6-A resolution of human macrophage migration inhibitory factor. Proc. Natl Acad. Sci. USA 93, 5191–5196 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Sugimoto, H. et al. Crystallization and preliminary X-ray analysis of human D-dopachrome tautomerase. J. Struct. Biol. 120, 105–108 (1997).

    CAS  PubMed  Google Scholar 

  33. Nishino, T. et al. Localization of MIF to secretory granules within the corticotrophic and thyrotrophic cells of the pituitary gland. Mol. Med. 1, 781–788 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Waeber, G. et al. Transcriptional activation of the macrophage migration-inhibitory factor gene by the corticotropin-releasing factor is mediated by the cyclic adenosine 3′,5′-monophosphate responsive element-binding protein CREB in pituitary cells. Mol. Endocrinol. 12, 698–705 (1998).

    CAS  PubMed  Google Scholar 

  35. Calandra, T. et al. MIF as a glucocorticoid-induced modulator of cytokine production. Nature 377, 68–71 (1995).

    CAS  PubMed  Google Scholar 

  36. Petrovsky, N. et al. Macrophage migration inhibitory factor (MIF) exhibits a pronounced circadian rhythm relevant to its role as a glucocorticoid counter-regulator. Immunol. Cell Biol. 81, 137–143 (2003).

    CAS  PubMed  Google Scholar 

  37. Calandra, T., Bernhagen, J., Mitchell, R. A. & Bucala, R. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J. Exp. Med. 179, 1895–1902 (1994).

    CAS  PubMed  Google Scholar 

  38. Bacher, M. et al. Migration inhibitory factor expression in experimentally induced endotoxemia. Am. J. Pathol. 150, 235–246 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Fingerle-Rowson, G. et al. Regulation of macrophage migration inhibitory factor expression by glucocorticoids in vivo. Am. J. Pathol. 162, 47–56 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Rhen, T. & Cidlowski, J. A. Antiinflammatory action of glucocorticoids — new mechanisms for old drugs. N. Engl. J. Med. 353, 1711–1723 (2005).

    CAS  PubMed  Google Scholar 

  41. Compton, M. M., Caron, L. A. & Cidlowski, J. A. Glucocorticoid action on the immune system. J. Steroid Biochem. 27, 201–208 (1987).

    CAS  PubMed  Google Scholar 

  42. Leech, M., Metz, C., Bucala, R. & Morand, E. F. Regulation of macrophage migration inhibitory factor by endogenous glucocorticoids in rat adjuvant-induced arthritis. Arthritis Rheum. 43, 827–833 (2000).

    CAS  PubMed  Google Scholar 

  43. Kevill, K. A. et al. A role for macrophage migration inhibitory factor in the neonatal respiratory distress syndrome. J. Immunol. 180, 601–608 (2008).

    CAS  PubMed  Google Scholar 

  44. Ji, N., Kovalovsky, A., Fingerle-Rowson, G., Guentzel, M. N. & Forsthuber, T. G. Macrophage migration inhibitory factor promotes resistance to glucocorticoid treatment in EAE. Neurol. Neuroimmunol. Neuroinflamm. 2, e139 (2015).

    PubMed  PubMed Central  Google Scholar 

  45. Daun, J. M. & Cannon, J. G. Macrophage migration inhibitory factor antagonizes hydrocortisone-induced increases in cytosolic IκB. Am. J. Physiol. 279, R1043–R1049 (2000).

    CAS  Google Scholar 

  46. Wang, F. F. et al. New insights into the role and mechanism of macrophage migration inhibitory factor in steroid-resistant patients with systemic lupus erythematosus. Arthritis Res. Ther. 14, R103–R112 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Roger, T., Chanson, A. L., Knaup-Reymond, M. & Calandra, T. Macrophage migration inhibitory factor promotes innate immune responses by suppressing glucocorticoid-induced expression of mitogen-activated protein kinase phosphatase-1. Eur. J. Immunol. 35, 3405–3413 (2005).

    CAS  PubMed  Google Scholar 

  48. Aeberli, D. et al. Endogenous macrophage migration inhibitory factor modulates glucocorticoid sensitivity in macrophages via effects on MAP kinase phosphatase-1 and p38 MAP kinase. FEBS Lett. 580, 974–981 (2006).

    CAS  PubMed  Google Scholar 

  49. Mitchell, R. A., Metz, C. N., Peng, T. & Bucala, R. Sustained mitogen-activated protein kinase (MAPK) and cytoplasmic phospholipase A2 activation by macrophage migration inhibitory factor (MIF). Regulatory role in cell proliferation and glucocorticoid action. J. Biol. Chem. 274, 18100–18106 (1999).

    CAS  PubMed  Google Scholar 

  50. Swantek, J. L., Cobb, M. H. & Geppert, T. D. Jun N-terminal kinase/stress activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha (TNF-α) translation: glucocorticoids inhibit TNF-α translation by blocking JNK/SAPK. Mol. Cell. Biol. 17, 6274–6282 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Foote, A. et al. Macrophage migration inhibitory factor in systemic lupus erythematosus. J. Rheumatol. 31, 268–273 (2004).

    CAS  PubMed  Google Scholar 

  52. Leng, L. et al. Glucocorticoid-induced MIF expression by human CEM T cells. Cytokine 48, 177–185 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Wintermantel, T. A., Berger, S., Erich, E. F. & Schutz, G. Evaluation of steroid receptor function by gene targeting in mice. J. Steroid Biochem. Mol. Biol. 93, 107–112 (2005).

    CAS  PubMed  Google Scholar 

  54. Flaster, H., Bernhagen, J., Calandra, T. & Bucala, R. The macrophage migration inhibitory factor-glucocorticoid dyad: regulation of inflammation and immunity. Mol. Endocrinol. 21, 1267–1280 (2007).

    CAS  PubMed  Google Scholar 

  55. Leng, L. et al. MIF signal transduction initiated by binding to CD74. J. Exp. Med. 197, 1467–1476 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Shi, X. et al. CD44 is the signaling component of the MIF-CD74 receptor complex. Immunity 25, 595–606 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Bucala, R. & Shachar, I. The integral role of CD74 in antigen presentation, MIF signal transduction, and B cell survival and homeostasis. Mini Rev. Med. Chem. 14, 1132–1138 (2014).

    CAS  PubMed  Google Scholar 

  58. Yoo, S. A. et al. MIF allele-dependent regulation of the MIF coreceptor CD44 and role in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 113, E7917–E7926 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Mitchell, R. A. et al. Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response. Proc. Natl Acad. Sci. USA 99, 345–350 (2002).

    CAS  PubMed  Google Scholar 

  60. Roger, T., David, J., Glauser, M. P. & Calandra, T. MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 414, 920–924 (2001).

    CAS  PubMed  Google Scholar 

  61. Amin, M. A. et al. Migration inhibitory factor up-regulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 via Src, PI3 kinase, and NFκB. Blood 107, 2252–2261 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Miller, E. J. et al. Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature 451, 578–582 (2008).

    CAS  PubMed  Google Scholar 

  63. Bernhagen, J. et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat. Med. 13, 587–596 (2007).

    CAS  PubMed  Google Scholar 

  64. Schneppenheim, J. et al. The intramembrane protease SPPL2A promotes B cell development and controls endosomal traffic by cleavage of the invariant chain. J. Exp. Med. 210, 41–58 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Lantner, F. et al. CD74 induces TAp63 expression leading to B cell survival. Blood 110, 4303–4311 (2007).

    CAS  PubMed  Google Scholar 

  66. Gil-Yarom, N. et al. CD74 is a novel transcription regulator. Proc. Natl Acad. Sci. USA 114, 562–567 (2017).

    CAS  PubMed  Google Scholar 

  67. Gore, Y. et al. Macrophage migration inhibitory factor (MIF) induces B cell survival by activation of a CD74/CD44 receptor complex. J. Biol. Chem. 283, 2784–2792 (2008).

    CAS  PubMed  Google Scholar 

  68. Gordin, M. et al. c-Met and its ligand hepatocyte growth factor/scatter factor regulate mature B cell survival in a pathway induced by CD74. J. Immunol. 185, 2020–2031 (2010).

    CAS  PubMed  Google Scholar 

  69. Merk, M. et al. The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF). Proc. Natl Acad. Sci. USA 108, E577–E585 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Merk, M., Mitchell, R. A., Endres, S. & Bucala, R. D-dopachrome tautomerase (D-DT or MIF-2): doubling the MIF cytokine family. Cytokine 59, 10–17 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Qi, D. et al. The vestigial enzyme D-dopachrome tautomerase protects the heart against ischemic injury. J. Clin. Invest. 124, 3540–3550 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Assis, D. N. et al. The role of macrophage migration inhibitory factor in autoimmune liver disease. Hepatology 59, 580–591 (2014).

    CAS  PubMed  Google Scholar 

  73. Wu, G. et al. Relationship between elevated soluble CD74 and severity of experimental and clinical ALI/ARDS. Sci. Rep. 6, 30067 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Kleemann, R. et al. Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature 408, 211–216 (2000).

    CAS  PubMed  Google Scholar 

  75. Shin, M. S. et al. Macrophage migration inhibitory factor regulates U1 small nuclear RNP immune complex-mediated activation of the NLRP3 inflammasome. Arthritis Rheum. 71, 109–120 (2019).

    CAS  Google Scholar 

  76. Lang, T. et al. Macrophage migration inhibitory factor is required for NLRP3 inflammasome activation. Nat. Commun. 9, 2223 (2018).

    PubMed  PubMed Central  Google Scholar 

  77. Chen, Z. & O’Shea, J. J. Regulation of IL-17 production in human lymphocytes. Cytokine 41, 71–78 (2008).

    PubMed  Google Scholar 

  78. Shin, M. S. et al. U1-small nuclear ribonucleoprotein activates the NLRP3 inflammasome in human monocytes. J. Immunol. 188, 4769–4775 (2012).

    CAS  PubMed  Google Scholar 

  79. So, A. K. & Martinon, F. Inflammation in gout: mechanisms and therapeutic targets. Nat. Rev. Rheumatol. 13, 639–647 (2017).

    CAS  PubMed  Google Scholar 

  80. Shin, M. S. et al. Self double-stranded (ds)DNA induces IL-1β production from human monocytes by activating NLRP3 inflammasome in the presence of anti-dsDNA antibodies. J. Immunol. 190, 1407–1415 (2013).

    CAS  PubMed  Google Scholar 

  81. Casciola-Rosen, L. A., Anhalt, G. & Rosen, A. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J. Exp. Med. 179, 1317–1330 (1994).

    CAS  PubMed  Google Scholar 

  82. Galvao, I. et al. Macrophage migration inhibitory factor drives neutrophil accumulation by facilitating IL-1β production in a murine model of acute gout. J. Leukoc. Biol. 99, 1035–1043 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Donn, R. P., Shelley, E., Ollier, W. E. & Thomson, W. A novel 5′-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 44, 1782–1785 (2001).

    CAS  PubMed  Google Scholar 

  84. Barton, A. et al. Macrophage migration inhibitory factor (MIF) gene polymorphism is associated with susceptibility to but not severity of inflammatory polyarthritis. Genes Immun. 4, 487–491 (2003).

    CAS  PubMed  Google Scholar 

  85. De Benedetti, F. et al. Functional and prognostic relevance of the -173 polymorphism of the MIF gene in systemic juvenile idiopathic arthritis. Arthritis Rheum. 48, 1398–1407 (2003).

    PubMed  Google Scholar 

  86. Yao, J. et al. Transcription factor ICBP90 regulates the MIF promoter and immune susceptibility locus. J. Clin. Invest. 126, 732–744 (2016).

    PubMed  PubMed Central  Google Scholar 

  87. Donn, R. P. et al. Macrophage migration inhibitory factor gene polymorphism is associated with psoriasis. J. Invest. Dermatol. 123, 484–487 (2004).

    CAS  PubMed  Google Scholar 

  88. Morales-Zambrano, R. et al. Macrophage migration inhibitory factor (MIF) promoter polymorphisms (-794 CATT5-8 and -173 G>C): association with MIF and TNFα in psoriatic arthritis. Int. J. Clin. Exp. Med. 7, 2605–2614 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Amoli, M. M. et al. Macrophage migration inhibitory factor gene polymorphism is associated with sarcoidosis in biopsy proven erythema nodosum. J. Rheumatol. 29, 1671–1673 (2002).

    CAS  PubMed  Google Scholar 

  90. Bossini-Castillo, L. et al. An MIF promoter polymorphism is associated with susceptibility to pulmonary arterial hypertension in diffuse cutaneous systemic sclerosis. J. Rheumatol. 44, 1453–1457 (2017).

    CAS  PubMed  Google Scholar 

  91. Le Hiress, M. et al. Proinflammatory signature of the dysfunctional endothelium in pulmonary hypertension. Role of the macrophage migration inhibitory factor/CD74 complex. Am. J. Respir. Crit. Care Med. 192, 983–997 (2015).

    PubMed  Google Scholar 

  92. Peterson, K. S. & Winchester, R. in Arthritis and Allied Conditions Vol. 15 (eds Koopman, W. J. & Moreland, L. W.) 1523–1574 (Lippincott Williams & Wilkins, 2005).

  93. Kim, W. U., Sreih, A. & Bucala, R. Toll-like receptors in systemic lupus erythematosus; prospects for therapeutic intervention. Autoimmun. Rev. 8, 204–208 (2009).

    CAS  PubMed  Google Scholar 

  94. Slight-Webb, S. et al. Autoantibody-positive healthy individuals display unique immune profiles that may regulate autoimmunity. Arthritis Rheum. 68, 2492–2502 (2016).

    CAS  Google Scholar 

  95. Das, R. et al. Macrophage migration inhibitory factor promotes clearance of pneumococcal colonization. J. Immunol. 193, 764–772 (2014).

    CAS  PubMed  Google Scholar 

  96. Colonna, L., Lood, C. & Elkon, K. B. Beyond apoptosis in lupus. Curr. Opin. Rheumatol. 26, 459–466 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Fingerle-Rowson, G. et al. The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting. Proc. Natl Acad. Sci. USA 100, 9354–9359 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Beisner, D. R. et al. The intramembrane protease SPPL2a is required for B cell and DC development and survival via cleavage of the invariant chain. J. Exp. Med. 210, 23–30 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Simonini, G. et al. Macrophage migration inhibitory factor -173 polymorphism and risk of coronary alterations in children with Kawasaki disease. Clin. Exp. Rheumatol. 27, 1026–1030 (2009).

    CAS  PubMed  Google Scholar 

  100. Vivarelli, M. et al. Macrophage migration inhibitory factor (MIF) and oligoarticular juvenile idiopathic arthritis (o-JIA): association of MIF promoter polymorphisms with response to intra-articular glucocorticoids. Clin. Exp. Rheumatol. 25, 775–781 (2007).

    CAS  PubMed  Google Scholar 

  101. Griga, T. et al. A polymorphism in the macrophage migration inhibitory factor gene is involved in the genetic predisposition of Crohn’s disease and associated with cumulative steroid doses. Hepatogastroenterology 54, 784–786 (2007).

    CAS  PubMed  Google Scholar 

  102. Berdeli, A. et al. Association of macrophage migration inhibitory factor -173C allele polymorphism with steroid resistance in children with nephrotic syndrome. Pediatr. Nephrol. 20, 1566–1571 (2005).

    PubMed  Google Scholar 

  103. McDevitt, M. A. et al. A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia. J. Exp. Med. 203, 1185–1196 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. McDevitt, M. A., Xie, J., Gordeuk, V. & Bucala, R. The anemia of malaria infection: role of inflammatory cytokines. Curr. Hematol. Rep. 3, 97–106 (2004).

    PubMed  Google Scholar 

  105. Jain, V. et al. Macrophage migration inhibitory factor is associated with mortality in cerebral malaria patients in India. BMC Res. Notes 2, 36 (2009).

    PubMed  PubMed Central  Google Scholar 

  106. Leech, M. et al. Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis. Arthritis Rheum. 48, 1881–1889 (2003).

    CAS  PubMed  Google Scholar 

  107. Mikulowska, A., Metz, C. N., Bucala, R. & Holmdahl, R. Macrophage migration inhibitory factor is involved in the pathogenesis of collagen type II-induced arthritis in mice. J. Immunol. 158, 5514–5517 (1997).

    CAS  PubMed  Google Scholar 

  108. Herrero, L. J. et al. MIF receptor CD74 mediates alphavirus-induced arthritis and myositis. Arthritis Rheum. 65, 2724–2736 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Singh, A. et al. Macrophage-derived MIF is sufficient to induce disease in the K/BxN serum-induced model of arthritis. Rheumatol. Int. 33, 2301–2308 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Morand, E. F. et al. Macrophage migration inhibitory factor in rheumatoid arthritis: clinical correlations. Rheumatology 41, 558–562 (2002).

    CAS  PubMed  Google Scholar 

  111. Kim, H. R. et al. Macrophage migration inhibitory factor upregulates angiogenic factors and correlates with clinical measures in rheumatoid arthritis. J. Rheumatol. 34, 927–936 (2007).

    CAS  PubMed  Google Scholar 

  112. Hernandez-Palma, L. A. et al. Functional MIF promoter haplotypes modulate Th17-related cytokine expression in peripheral blood mononuclear cells from control subjects and rheumatoid arthritis patients. Cytokine 115, 89–96 (2018).

    PubMed  Google Scholar 

  113. Sampey, A. V., Hall, P. H., Mitchell, R. A., Metz, C. N. & Morand, E. F. Regulation of synoviocyte phospholipase A2 and cyclooxygenase 2 by macrophage migration inhibitory factor. Arthritis Rheum. 44, 1273–1280 (2001).

    CAS  PubMed  Google Scholar 

  114. Lacey, D. et al. Control of fibroblast-like synoviocyte proliferation by macrophage migration inhibitory factor. Arthritis Rheum. 48, 103–109 (2003).

    CAS  PubMed  Google Scholar 

  115. Onodera, S. et al. Macrophage migration inhibitory factor up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis. J. Biol. Chem. 275, 444–450 (2000).

    CAS  PubMed  Google Scholar 

  116. Pakozdi, A. et al. Macrophage migration inhibitory factor: a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis. Arthritis Res. Ther. 8, R132–R145 (2006).

    PubMed  PubMed Central  Google Scholar 

  117. Amin, M. A. et al. Migration inhibitory factor mediates angiogenesis via mitogen-activated protein kinase and phosphatidylinositol kinase. Circ. Res. 93, 321–329 (2003).

    CAS  PubMed  Google Scholar 

  118. Elsby, L. A. et al. Hypoxia and glucocorticoid signaling converge to regulate MIF gene expression. Arthritis Rheum. 60, 2220–2231 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. You, S., Koh, J. H., Leng, L., Kim, W. U. & Bucala, R. The tumor-like phenotype of rheumatoid synovium: molecular profiling and prospects for precision medicine. Arthritis Rheum. 70, 637–652 (2018).

    CAS  Google Scholar 

  120. Fan, H. et al. Macrophage migration inhibitory factor and CD74 regulate macrophage chemotactic responses via MAPK and Rho GTPase. J. Immunol. 186, 4915–4924 (2011).

    CAS  PubMed  Google Scholar 

  121. Gu, R. et al. Macrophage migration inhibitory factor is essential for osteoclastogenic mechanisms in vitro and in vivo mouse model of arthritis. Cytokine 72, 135–145 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Bottini, N. & Firestein, G. S. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat. Rev. Rheumatol. 9, 24–33 (2013).

    CAS  PubMed  Google Scholar 

  123. Ponta, H., Sherman, L. & Herrlich, P. A. CD44: from adhesion molecules to signalling regulators. Nat. Rev. Mol. Cell Biol. 4, 33–45 (2003).

    CAS  PubMed  Google Scholar 

  124. Katagiri, Y. U. et al. CD44 variants but not CD44s cooperate with beta1-containing integrins to permit cells to bind to osteopontin independently of arginine-glycine-aspartic acid, thereby stimulating cell motility and chemotaxis. Cancer Res. 59, 219–226 (1999).

    CAS  PubMed  Google Scholar 

  125. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  126. Bucala, R. & Donnelly, S. C. Macrophage migration inhibitory factor: a probable link between inflammation and cancer. Immunity 26, 281–285 (2007).

    CAS  PubMed  Google Scholar 

  127. Petrenko, O. & Moll, U. M. Macrophage migration inhibitory factor MIF interferes with the Rb-E2F pathway. Mol. Cell 17, 225–236 (2005).

    CAS  PubMed  Google Scholar 

  128. Talos, F., Mena, P., Fingerle-Rowson, G., Moll, U. & Petrenko, O. MIF loss impairs Myc-induced lymphomagenesis. Cell Death Differ. 12, 1319–1328 (2005).

    CAS  PubMed  Google Scholar 

  129. Bloom, B. R. & Bennett, B. Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science 153, 80–82 (1966).

    CAS  PubMed  Google Scholar 

  130. Lan, H. Y. et al. Expression of macrophage migration inhibitory factor in human glomerulonephritis. Kidney Int. 57, 499–509 (2000).

    CAS  PubMed  Google Scholar 

  131. Djudjaj, S. et al. Macrophage migration inhibitory factor mediates proliferative GN via CD74. J. Am. Soc. Nephrol. 27, 1650–1664 (2016).

    CAS  PubMed  Google Scholar 

  132. Hoi, A. Y. et al. Macrophage migration inhibitory factor deficiency attenuates macrophage recruitment, glomerulonephritis, and lethality in MRL/lpr mice. J. Immunol. 177, 5687–5696 (2006).

    CAS  PubMed  Google Scholar 

  133. Leng, L. et al. A small-molecule macrophage migration inhibitory factor antagonist protects against glomerulonephritis in lupus-prone NZB/NZW F1 and MRL/ lpr mice. J. Immunol. 186, 527–538 (2011).

    CAS  PubMed  Google Scholar 

  134. Sapoznikov, A. et al. Perivascular clusters of dendritic cells provide critical survival signals to B cells in bone marrow niches. Nat. Immunol. 9, 388–395 (2008).

    CAS  PubMed  Google Scholar 

  135. US National Library of Medicine. ClnicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01541670 (2017).

  136. Mahalingam, D. et al. Safety and efficacy of imalumab, an anti-macrophage migration inhibitory factor antibody, alone or in combination with 5-fluorouracil/leucovorin or panitumumab, in patients with metastatic colorectal cancer. Ann. Oncol. 27, 102–117 (2016).

    Google Scholar 

  137. Wallace, D. J., Wegener, W. A., Horne, H. & Goldenberg, D. M. CT-01 phase IB study of IMMU-115 (humanised anti-CD74 antibody) targeting antigen presenting cells in patients with systemic lupus erythematosus (SLE). Lupus Sci. Med. 3 (Suppl. 1), A37 (2016).

    Google Scholar 

  138. Bauer, J. W. et al. Interferon-regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: a validation study. Arthritis Rheum. 60, 3098–3107 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Connelly, K. L., Kandane-Rathnayake, R., Hoi, A., Nikpour, M. & Morand, E. F. Association of MIF, but not type I interferon-induced chemokines, with increased disease activity in Asian patients with systemic lupus erythematosus. Sci. Rep. 6, 29909 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Ranganathan, V. et al. Macrophage migration inhibitory factor induces inflammation and predicts spinal progression in ankylosing spondylitis. Arthritis Rheumatol. 69, 1796–1806 (2017).

    CAS  PubMed  Google Scholar 

  141. Elke, R. et al. Sensitivity and specificity of autoantibodies against CD74 in axial spondyloarthritis. Arthritis Rheum. 71, 729–735 (2018).

    Google Scholar 

  142. Alinari, L. et al. Combination anti-CD74 (milatuzumab) and CD20 (rituximab) monoclonal antibody therapy has in vitro and in vivo activity in mantle cell lymphoma. Blood 117, 4530–4541 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Liu, X. et al. Development of a phase Ib/IIa proof-of-concept study of imalumab (BAX69), a first-in-class anti-macrophage migration inhibitory factor (MIF) antibody, as the 3rd or 4th line treatment in metastatic colorectal cancer (mCRC) [abstract]. J. Clin. Oncol. 33 (Suppl. 15), TPS3633 (2015).

    Google Scholar 

  144. Pantouris, G. et al. An analysis of MIF structural features that control functional activation of CD74. Chem. Biol. 22, 1197–1205 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Fingerle-Rowson, G. et al. A tautomerase-null MIF gene knock-in mouse model reveals that protein interactions and not enzymatic activity mediate MIF-dependent growth regulation. Mol. Cell. Biol. 29, 1922–1932 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Orita, M., Yamamoto, S., Katayama, N. & Fujita, S. Macrophage migration inhibitory factor and the discovery of tautomerase inhibitors. Curr. Pharm. Res. 8, 1297–1317 (2002).

    CAS  Google Scholar 

  147. Lubetsky, J. B. et al. The tautomerase active site of macrophage migration inhibitory factor is a potential target for discovery of novel anti-inflammatory agents. J. Biol. Chem. 277, 24976–24982 (2002).

    CAS  PubMed  Google Scholar 

  148. Cournia, Z. et al. Discovery of human MIF-CD74 antagonists via virtual screening. J. Med. Chem. 52, 416–424 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Hare, A. A. et al. Optimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF). Bioorg. Med. Chem. Lett. 20, 5811–5814 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Cho, Y. et al. Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast. Proc. Natl Acad. Sci. USA 107, 11313–11318 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Fox, R. J. et al. Phase 2 trial of ibudilast in progressive multiple sclerosis. N. Engl. J. Med. 379, 846–855 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Benedek, G. et al. MIF and D-DT are potential disease severity modifiers in male MS subjects. Proc. Natl Acad. Sci. USA 114, E8421–E8429 (2017).

    Google Scholar 

  153. Pantouris, G. et al. Nanosecond dynamics regulate the MIF-induced activity of CD74. Angew. Chem. Int. Ed. Engl. 57, 7116–7119 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Jorgensen, W. L. et al. Receptor agonists of macrophage migration inhibitory factor. Bioorg. Med. Chem. Lett. 20, 7033–7036 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Wang, J. et al. Limiting cardiac ischemic injury by pharmacologic augmentation of MIF-AMPK signal transduction. Circulation 128, 225–236 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Shachar, I. et al. in The MIF Handbook 1st edn (ed. Bucala, R.) 55–76 (World Scientific, 2012).

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Acknowledgements

The authors are grateful to the members of their laboratories and to the participants of the 9th International MIF Symposium (Munich, Germany, 2018) for many helpful discussions on MIF biology. I.K. and R.B. acknowledge that their research is funded by the US NIH.

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  1. Section of Rheumatology, Allergy, and Immunology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

    Insoo Kang & Richard Bucala

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I.K. and R.B. reviewed the literature and wrote the manuscript.

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Correspondence to Richard Bucala.

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R.B. declares that he is a co-inventor on patents for MIF antagonists and MIF genotyping. I.K. declares no competing interests.

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Kang, I., Bucala, R. The immunobiology of MIF: function, genetics and prospects for precision medicine. Nat Rev Rheumatol 15, 427–437 (2019). https://doi.org/10.1038/s41584-019-0238-2

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