Brain miffed by macrophage migration inhibitory factor

Abstract

Macrophage migration inhibitory factor (MIF) is a cytokine which also exhibits enzymatic properties like oxidoreductase and tautomerase. MIF plays a pivotal role in innate and acquired immunity as well as in the neuroendocrine axis. Since it is involved in the pathogenesis of acute and chronic inflammation, neoangiogenesis, and cancer, MIF and its signaling components are considered suitable targets for therapeutic intervention in several fields of medicine. In neurodegenerative and neurooncological diseases, MIF is a highly relevant, but still a hardly investigated mediator. MIF operates via intracellular protein-protein interaction as well as in CD74/CXCR2/CXCR4 receptor-mediated pathways to regulate essential cellular systems such as redox balance, HIF-1, and p53-mediated senescence and apoptosis as well as multiple signaling pathways. Acting as an endogenous glucocorticoid antagonist, MIF thus represents a relevant resistance gene in brain tumor therapies. Alongside this dual action, a functional homolog-annotated D-dopachrome tautomerase/MIF-2 has been uncovered utilizing the same cell surface receptor signaling cascade as MIF. Here we review MIF actions with respect to redox regulation in apoptosis and in tumor growth as well as its extracellular function with a focus on its potential role in brain diseases. We consider the possibility of MIF targeting in neurodegenerative processes and brain tumors by novel MIF-neutralizing approaches.

Figure 1

MIF, DDT, and CD74 distribution in human tissues. Comparative analysis of MIF, DDT (MIF-2), and its receptor CD74 expression in various human tissues. For human mRNA expression analysis, the BioGPS database (http://biogps.gnf.org profile graph) with the Affymetrix chip Human U133A was acquired. Note in particular the different expression values of MIF and DDT in brain tissue. For details on the Affymetrix chip analysis, see [37, 38].

Figure 2

Structural homologies of MIF and DDT. (a) Primary structural scheme of the human MIF gene. Yellow region indicates the CXXC domain, the blue boxed domains indicate the proposed tautomerase/isomerase domains and clustered amino acids (Phe3, Val39, Gly50, Lys66, Asn102, Gly107, Trp108, Phe113, and Ala114) [18]. (b) Structural comparison of human MIF and DDT trimers. The catalytically important CXXC domain is shown in yellow. β-sheets are given as arrows, and α-sheets are shown as columns. Data were obtained from the NCBI database (http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=89970) based on the study of [28].

Figure 3

MIF and DDT distribution in the brain. Representative in situ hybridization images of MIF mRNA (a) and DDT mRNA distribution (b) in adult mouse brain (left) with consecutive counterstained brain section (Nissl stain, right). Upper panels of (a) and (b) represent coronal plane; lower panels show sagittal plane. Data were provided from the Allan Brain Atlas website (http://www.brain-map.org/), and the Brain Explorer 1.3 software was utilized for the visualization of gene expression [39].

Figure 4

MIF receptor signalling and downstream effectors. (a) Schematic model of receptor-mediated MIF signalling involving CD74 and CXCRs. The involvement of the glutamate antiporter xCT (system x_c ⁻, xCT forms a heterodimer with CD98 as indicated) in CD74/CD44-dependent signalling is proposed, indicated by the dotted arrow. (b) MIF binding partners with link to brain cancer. Note that the indicated MIF-binding partners given in the scheme are far from complete. Abbreviations used: COX2, cyclooxygenase 2; ERK, extracellular signal-regulated kinases; GC, glucocorticoids; GR, glucocorticoid receptor; GEF, guanosine exchange factor; HIF1α, hypoxy Jab1, Jun-activation domain-binding protein-1; MKP1, mitogen-activated protein kinase phosphatases; MMP-9, matrix metallopeptidase or type IV collagenase/gelatinase B; PRDX, peroxiredoxin; Src, sarcoma protooncogene.

Figure 5

The brain tumor microenvironment, heterogeneous tumor zones and MIF actions. Conceptual framework depicting the metabolic and immune cell complexity of malignant brain tumors, (glioblastomas, GBM) is given as a simplified model classifying the tumor into three distinct tumor zones (TZ1–TZ3). Tumor Zone 1 (TZ1) consists of the main tumor—bulk and core glioma cells, corresponding to contrast enhancing regions in MRI images. MIF is mainly produced in TZ1 and secreted into the extracellular space. TZ2 represents the area of perifocal edema, which is characterized by its specific proangiogenic microenvironment and presence of transitory glioma cells. In addition, this tumor zone shows pronounced accumulation of microglial cells, which also infiltrate TZ1. TZ3 is the most awkward zone for therapeutic intervention, since this tumor zone consists mainly of healthy brain parenchyma. However, isolated glioma-initiating cells termed partisan cells colonize TZ3 and are most probably responsible for tumor recurrence following surgery. TZ2 is probably biologically most active, influencing TZ1 and TZ3 by tumor-derived metabolites impacting the immune system, angiogenesis, and cell fate.