title: A role for macrophage migration inhibitory factor in protective immunity against Aspergillus fumigatus.
abstract: Inflammation plays an important role in protective immunity against fungi, including the opportunistic pathogen, Aspergillus fumigatus. The balance between pro-inflammatory and anti-inflammatory cytokines is a key determinant of infection outcome. Since macrophage migration inhibitory factor (MIF) is an upstream regulator of many cytokines, we analyzed herein the role of endogenous MIF in the host control of hematogenously disseminated aspergillosis using MIF⁻/⁻ mice. As revealed by their mortality rate, MIF⁻/⁻ mice were more susceptible to disseminated infection than WT mice. Moreover, pharmacologic inhibition of MIF with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester, (ISO-1) increased the susceptibility of WT mice to lethal infection. The higher tissue fungal burden early in sublethal infection indicated increased susceptibility of MIF⁻/⁻ mice to sublethal infection as well. Substantial down-regulation of innate and acquired antifungal responses, characterized by decreased production of IL-1β, IL-6, TNF-α, IFN-γ and IL-17 in the spleen was noted in sublethally infected MIF⁻/⁻ mice. In contrast, IL-4 was higher in MIF⁻/⁻ than in WT mice. Taken together, our findings show that MIF contributes to host resistance against progressive invasive A. fumigatus infection by controlling downstream pro-inflammatory versus anti-inflammatory cytokine production thus determining the outcome of infection.
authors.affiliation: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Stojanovic
authors.forename: Ivana
authors.initials: I
authors.lastname: Mirkov
authors.forename: Milena
authors.initials: M
authors.lastname: Kataranovski
authors.forename: Jasmina
authors.initials: J
authors.lastname: Glamoclija
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stosic-Grujicic
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001228:Aspergillosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001232:Aspergillus fumigatus / Q000254:growth & development / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D007555:Isoxazoles / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D016207:Cytokines; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse