Macrophage migration inhibitory factor triggers chemotaxis of CD74+CXCR2+NKT cells in chemically induced IFN-γ-Mediated skin inflammation

Chia Yuan Hsieh, Chia Ling Chen, Yee Shin Lin, Trai Ming Yeh, Tsung Ting Tsai, Ming Yuan Hong, Chiou Feng Lin

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)


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-Otetradecanoylphorbol- 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 theMIF 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 TPAinduced 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.

Original languageEnglish
Pages (from-to)3693-3703
Number of pages11
JournalJournal of Immunology
Issue number7
Publication statusPublished - 2014 Oct 1

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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