MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics

Abstract

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with chemokine-like functions that increasingly is being studied in different aspects of cardiovascular disease. MIF was first identified as a proinflammatory and pro-survival mediator within the immune system, and a second structurally related MIF family member, D-dopachrome tautomerase (a.k.a. MIF-2), was reported recently. Both MIF family members are released by myocardium and modulate the manifestations of cardiovascular disease, specifically in myocardial ischemia. Areas covered: A scientific overview is provided for the involvement of MIF family cytokines in the inflammatory pathogenesis of atherosclerosis, myocardial infarction, and ischemia-reperfusion injury. We summarize findings of experimental, human genetic and clinical studies, and suggest therapeutic opportunities for modulating the activity of MIF family proteins that potentially may be applied in a MIF allele specific manner. Expert opinion: Knowledge of MIF, MIF-2 and their receptor pathways are under active investigation in different types of cardiovascular diseases, and novel therapeutic opportunities are being identified. Clinical translation may be accelerated by accruing experience with MIF-directed therapies currently in human testing in cancer and autoimmunity.

Keywords: Atherosclerosis; CD74; CXCR2; CXCR4; D-dopachrome tautomerase; ischemia reperfusion; macrophage migration inhibitory factor; myocardial infarction.

Fig. 1:. MIF protein family homology.

The significant similarity between the three-dimensional X-ray crystal structures of human MIF and human MIF-2. (A) Left panel: Human MIF monomer, Right panel: Human MIF trimer. (B) Left panel: Human MIF-2 monomer, Right panel: Human MIF-2 trimer. Structures reused from “Merk M, Mitchell RA, Endres S, Bucala R. D-dopachrome tautomerase (D-DT or MIF-2): doubling the MIF cytokine family. Cytokine. 2012;59:10–7. Epub 2012/04/18. http://www.sciencedirect.com/science/article/pii/S104346661200097X“

Fig. 2:. MIF family receptor signaling pathways in myocardial ischemia reperfusion and atherosclerosis.

Both MIF and MIF-2 bind to CD74, which results in its phosphorylation and the recruitment of CD44 into a signaling complex and MIF additionally signals through the chemokine receptors CXCR2 and CXCR4. Signaling through CD74/CD44 leads to apoptosis inhibition and metabolic adaptation resulting in cardioprotection. MIF interaction with the non-cognate receptors CXCR2 and CXCR4 modulates the migration of leukocytes and their migration arrest to chemokine stimulus at sites of inflammation. Figure compiled from references [41, 42].

Fig. 3:. The human MIF gene.

Shown is the human MIF locus with its three exons, the microsatellite −794 CATT_5–8, and the ICBP90 transcription factor binding site. Also shown is the - 173*G/C SNP that is in linkage with −794 CATT₇.

Fig. 4:. MIF and MIF-2 cardioprotective CD74/AMPK signaling.

Hypoxia resulting from ischemic stress releases intracellular MIF. MIF and MIF-2 activate the cardioprotective AMPK signaling pathway in aCD74:CD44 dependent manner. Activation of AMPK promotes cellular glucose uptake by inducing the trafficking of GLUT4-containing membrane vesicles to the membrane, inhibits pro-apoptotic cascades and enhances pro-survival signaling. Figure compiled from references [82, 101, 129].

Fig. 5:. MIF agonists enhance MIF binding to its receptor, CD74.

(A) Chemical structures of three different MIF agonists MIF20, MIF21 and MIF33. (B) MIF binding to immobilized soluble CD74 (sCD74=CD74^73–232) in the presence of increasing concentrations of MIF agonists. (C) Biacore analysis and MIF/sCD74 equilibrium constants. MIF introduced into the flow phase with vehicle (upper panel) or MIF20 (lower panel). Figures A-C reused from “Wang J, Tong C, Yan X, Yeung E, Gandavadi S, Hare AA, Du X, Chen Y, Xiong H, Ma C, Leng L, Young LH, Jorgensen WL, Li J, Bucala R. Limiting cardiac ischemic injury by pharmacological augmentation of macrophage migration inhibitory factor-AMP-activated protein kinase signal transduction. Circulation. 2013;128:225–36. http://circ.ahajournals.org/content/128/3/225.long” (D) Computational model showing three MIF20 molecules bound within the MIF tautomerase site, which forms at the interface of two adjacent monomers. (E) Computational model showing MIF interaction with three MIF receptor (CD74) proteins forming a dodecamer. Model taken from “Meza-Romero R, Benedek G, Leng L, Bucala R, Vandenbark AA. Predicted structure of MIF/CD74 and RTL1000/CD74 complexes. Metab Brain Dis. 2016;31:249–55. http://link.springer.com/article/10.1007/s11011-016-9798-x”.