The Dichotomic Role of Macrophage Migration Inhibitory Factor in Neurodegeneration

Abstract

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine expressed by different cell types and exerting multiple biological functions. It has been shown that MIF may be involved in several disorders, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), and Huntington disease (HD), that represent an unmet medical need. Therefore, further studies are needed to identify novel pathogenetic mechanisms that may translate into tailored therapeutic approaches so to improve patients' survival and quality of life. Here, we reviewed the preclinical and clinical studies investigating the role of MIF in ALS, PD, and HD. The emerging results suggest that MIF might play a dichotomic role in these disorders, exerting a protective action in ALS, a pathogenetic action in HD, and a yet undefined and debated role in PD. The better understanding of the role of MIF in these diseases could allow its use as a novel diagnostic and therapeutic tool for the monitoring and treatment of the patients and for eventual biomarker-driven therapeutic approaches.

Keywords: Huntington disease; Parkinson disease; amyotrophic lateral sclerosis; macrophage migration inhibitory factor; neurodegeneration.

Figure 1

MIF in ALS. Preclinical studies on MIF in ALS which show the results obtained in vitro and in vivo and the correlation between MIF chaperone activity and its protective effect against mutant SOD1 toxicity in motor neurons. MIF also inhibits the activation of pro-apoptotic mitochondrial pathway, blocking misfolded SOD1 interactions with outer mitochondrial membrane proteins, such as Bcl-2 and VDAC [38].

Figure 2

MIF in PD. Preclinical studies on MIF in PD, which show the results obtained in vitro and in vivo studies and the different pathway of how MIF could exert its protective function to inhibit neuronal loss. MIF mediates a neuroprotective effect via suppressing inflammatory responses, reducing the number of microglia and macrophages and displaying tyrosine hydroxylase-immunoreactive (TH-IR) neurons’ enhanced fiber outgrowth [49]. MIF also inhibits apoptosis and neuronal loss, detoxifying catecholamine-derived [15] and also promoting BDNF expression [50], increasing MMP and decreasing cleaved-PARP [47].

Figure 3

MIF in HD. Preclinical studies on MIF in HD show that lymphocytes of HD patients express MIF against a single agent present in brain samples of HD patients [59]. It has also been observed that MIF down expression, through the inhibition pathway of HDAC3, reduces the activation of the astrocytic response [60].