Pathogenic contribution of the Macrophage migration inhibitory factor family to major depressive disorder and emerging tailored therapeutic approaches

Background: Immunoinflammatory disorders are often accompanied by depression. Here, we review the available preclinical and clinical studies suggesting a role for the pro-inflammatory cytokine Macrophage migration inhibitory factor (MIF) and the second member of the MIF family, D-dopachrome tautomerase (D-DT; DDT), in the pathogenesis of Major Depressive Disorders (MDD). Methods: We prepared a narrative review from a search on PubMed of studies pertaining to MDD and MIF, as for October 2019. Both humans and animal studies haves been considered. Results: Preclinical data show conflicting results on the role of endogenous MIF and DDT in depression. In contrast, several human studies show that circulating MIF levels tend to increase during the course of MDD. Higher levels of inflammatory biomarkers have also been associated with poorer responses to antidepressants and the levels of MIF significantly decrease after treatment, despite this may not be necessarily associated to an improvement in psychiatric symptoms. Limitations: This is a narrative and not a systematic review of the literature on the involvement of MIF in MDD. We have highlighted studies performed in humans and in animal models, irrespective of population size and methodological approach. Conclusions: This review highlights a role of MIF, and possibly DDT, in the pathogenesis of MDD. Whilst studies in animal models are discordant, the studies in patients with MDD convergently suggest that MIF plays a role in induction and maintenance of the disease. Additional studies are also needed on DDT that often displays synergistic function with MIF and their receptors.