Review Article Macrophage migration inhibitory factor: A multifaceted cytokine implicated in multiple neurological diseases Marcel F. Leyton-Jaimes a , Joy Kahn a , Adrian Israelson a,b, ⁎ a Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer Sheva 84105, Israel b The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, P.O.B. 653, Beer Sheva 84105, Israel abstract article info Article history: Received 30 April 2017 Received in revised form 6 June 2017 Accepted 21 June 2017 Available online 2 July 2017 Macrophage migration inhibitory factor (MIF) is a conserved cytokine found as a homotrimer protein. It is found in a wide spectrum of cell types in the body including neuronal and non-neuronal cells. MIF is implicated in sev- eral biological processes; chemo-attraction, cytokine activity, and receptor binding, among other functions. More recently, a chaperone-like activity has been added to its repertoire. In this review, we focus on the implication of MIF in the central nervous system and peripheries, its role in neurological disorders, and the mechanisms by which MIF is regulated. Numerous studies have associated MIF with various disease settings. MIF plays an impor- tant role in advocating tumorigenic processes, Alzheimer's disease, and is also upregulated in autism-spectrum disorders and spinal cord injury where it contributes to the severity of the injured area. The protective effect of MIF has been reported in amyotrophic lateral sclerosis by its reduction of aggregated misfolded SOD1, subse- quently reducing the severity of this disease. Interestingly, a protective as well as pathological role for MIF has been implicated in stroke and cerebral ischemia, as well as depression. Thus, the role of MIF in neurological dis- orders appears to be diverse with both beneficial and adversary effects. Furthermore, its modulation is rather complex and it is regulated by different proteins, either on a molecular or protein level. This complexity might be dependent on the pathophysiological context and/or cellular microenvironment. Hence, further clarification of its diverse roles in neurological pathologies is warranted to provide new mechanistic insights which may lead in the future to the development of therapeutic strategies based on MIF, to fight some of these neurological disorders. © 2017 Elsevier Inc. All rights reserved. Keywords: MIF Central nervous system Neurological diseases Neurodegeneration Contents 1. MIF structure and function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 2. MIF expression in the central nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 3. MIF in neurological disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 3.1. MIF in brain tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 3.2. Spinal cord injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 3.3. Stroke and cerebral ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 3.4. Alzheimer's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 4. MIF in mental disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 4.1. Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 5. MIF in developmental disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 5.1. Autism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 6. MIF as a chaperone for misfolded SOD1 in amyotrophic lateral sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Experimental Neurology 301 (2018) 83–91 ⁎ Corresponding author at: Dept. of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer Sheva 84105, Israel. E-mail address: adriani@bgu.ac.il (A. Israelson). http://dx.doi.org/10.1016/j.expneurol.2017.06.021 0014-4886/© 2017 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr