Macrophage Migration Inhibitory Factor Triggers Chemotaxis of CD74+CXCR2+ NKT Cells in Chemically Induced IFN-γ–Mediated Skin Inflammation

Abstract

IFN-γ mediates chemically induced skin inflammation; however, the mechanism by which IFN-γ–producing cells are recruited to the sites of inflammation remains undefined. Secretion of macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, from damaged cells may promote immune cell recruitment. We hypothesized that MIF triggers an initial step in the chemotaxis of IFN-γ–producing cells in chemically induced skin inflammation. Using acute and chronic models of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in mouse ears, MIF expression was examined, and its role in this process was investigated pharmacologically. The cell populations targeted by MIF, their receptor expression patterns, and the effects of MIF on cell migration were examined. TPA directly caused cytotoxicity accompanied by MIF release in mouse ear epidermal keratinocytes, as well as in human keratinocytic HaCaT cells. Treatment with the MIF antagonist (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester considerably attenuated TPA-induced ear swelling, leukocyte infiltration, epidermal cell proliferation, and dermal angiogenesis. Inhibition of MIF greatly diminished the dermal infiltration of IFN-γ+ NKT cells, whereas the addition of exogenous TPA and MIF to NKT cells promoted their IFN-γ production and migration, respectively. MIF specifically triggered the chemotaxis of NKT cells via CD74 and CXCR2, and the resulting depletion of NKT cells abolished TPA-induced skin inflammation. In TPA-induced skin inflammation, MIF is released from damaged keratinocytes and then triggers the chemotaxis of CD74+CXCR2+ NKT cells for IFN-γ production.

New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model

“…These unconventional ligands vary widely in size, ranging from large proteins ( e.g. > 100 kDa) to peptides, and often have no sequence or structural similarities with chemokines [15, 169, 208, 209]. Despite their structural dissimilarities, non-chemokine CKR ligands can trigger signaling pathways similar to those induced by endogenous chemokines, although in some cases they initiate unconventional signaling responses [15, 169, 208–212].…”

“…More recently, the pseudo-chemokine MIF (macrophage migration inhibitory factor), a pleiotropic and proinflammatory chemotactic cytokine of 12.3 kDa highly expressed by tumor cells, has been identified as a ligand for CXCR2 [209], CXCR4 [169] and ACKR3 [210], inducing ERK1/2 and ZAP-70 signaling and chemotaxis. As with gp120, the binding of MIF to CKRs requires a primary receptor, CD74, a single segment membrane-spanning protein also known as HLA class II histocompatibility antigen gamma chain (Fig 4G).…”

The Diaeventology of Anxiety Disorders

“…The macrophage migration inhibitory factor (MIF) is a pro-inflammatory macrophage-specific cytokine that is active in the HPA axis and characterized haplotype variants of that gene were linked to diminished expression and lowered adolescent anxiety disorder [8]. MIF has been linked to the recruitment of natural killer T cells via an IFN-γ gradient in skin lesions, thus suggesting a similar role in causing the migration and stimulation of inflammatory leucocytes in the HPA axis [9].…”

Structural basis for decreased induction of class IB PI3‐kinases expression by MIF inhibitors

“…Macrophage migration inhibitory factor (MIF) is expressed at high levels in various inflammatory diseases and cancer [1]. Macrophage migration inhibitory factor promotes directional cell migration (or chemotaxis) of various cell types [2][3][4]. The mechanism underlying chemotaxis entails MIF activation of phosphoinositide 3-kinases (PI3Ks) that are upstream activators of the pleckstrin homology domain-containing protein kinase B (AKT) pathway [5].…”

“…In particular, maximal activation of p110c is associated with p101 [12,18], whereas other catalytic subunits are negatively regulated by p85 [19,20]. However, it is controversial as to whether Class IA or Class IB is the major isoform involved in the production of phosphatidylinositol (3,4,5)-trisphosphate and the activation of downstream signalling pathways [21,22].…”