Abstract
Macrophage migration inhibitory factor (MIF) is an immunoregulatory cytokine that has been extensively characterized in human disease and in mouse models. Its pro-inflammatory functions in mammals includes the retention of tissue macrophages and a unique ability to counteract the immunosuppressive activity of glucocorticoids. MIF also acts as a survival factor by preventing activation-induced apoptosis and by promoting sustained expression of inflammatory factors such as TNF-α and nitric oxide. The pro-inflammatory activity of MIF has been shown to be protective against Leishmania major infection in mouse models of cutaneous disease, however the precise role of this cytokine in human infections is less clear. Moreover, various species of Leishmania produce their own MIF orthologs, and there is evidence that these may drive an inflammatory environment that is detrimental to the host response. Herein the immune response to Leishmania in mouse models and humans will be reviewed, and the properties and activities of mammalian and Leishmania MIF will be integrated into the current understandings in this field. Furthermore, the prospect of targeting Leishmania MIF for therapeutic purposes will be discussed.
Highlights
The immune response during leishmaniasis has been actively studied for many years, and significant contributions to the field of immunology have been made in the study of the host response to Leishmania infection
In mouse models of leishmaniasis a protective immune response depends on a finely tuned Th1-type T cell response in order to direct macrophage killing of internalized parasites, and excessive inflammation can lead to T cell exhaustion and death, preventing sustained immunity
In humans a Th1-type response appears to be protective in cutaneous disease, excessive inflammation and T cell activity is associated with worsened visceral and diffuse disease., migration inhibitory factor (MIF) is an inflammatory cytokine produced by mammalian immune effector cells that can promote CD4 T cell and macrophage activity, and has been shown to enhance clearance of L. major parasites in vitro and in vivo, and ameliorate disease in a mouse model of cutaneous leishmaniasis
Summary
The immune response during leishmaniasis has been actively studied for many years, and significant contributions to the field of immunology have been made in the study of the host response to Leishmania infection. IFN-γ signaling is crucial for classical activation of macrophages and dendritic cells, driving production of NO and elimination of internalized parasites [7,9] This mechanism is well described in the C57BL/6 mouse model of infection. In more severe forms of the disease including diffuse cutaneous, mucocutaneous, and visceral leishmaniasis, excessive production of inflammatory cytokines including IFN-γ, TNF-α and IL-17 may be associated with more severe disease [26,27,28,29] These findings in humans and canines contrast with mouse models and suggest that a Th1-type response may not be entirely deleterious to parasite growth. In light of these studies it has been proposed that malaria infection has driven the preponderance of low-expression MIF alleles in sub-Saharan African populations in comparison with Caucasians [54]
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