Macrophage migration inhibitory factor (MIF) is essential for Type 2 effector cell immunity to an intestinal helminth parasite

Kara J. Filbey, Fumi Varyani, Yvonne Harcus, James Philip Hewitson, Danielle J. Smyth, Henry J. McSorley, Alasdair Ivens, Susanne Nylén, Martin Rottenberg, Stephan Loser, Rick M. Maizels

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Immunity to intestinal helminths is known to require both innate and adaptive components of the immune system activated alongthe Type 2 IL-4R/STAT6-dependent pathway. We have found that macrophage migration inhibitory factor (MIF) is essential for thedevelopment of effective immunity to the intestinal helminth Heligmosomoides polygyrus, even following vaccination which inducessterile immunity in wild-type mice. A chemical inhibitor of MIF, 4-IPP, was similarly found to compromise anti-parasite immunity.Cellular analyses found that the adaptive arm of the immune response, including IgG1 antibody responses and Th2-derivedcytokines, was intact and that Foxp3+ T regulatory cell responses were unaltered in the absence of MIF. However, MIF was found tobe an essential cytokine for innate cells, with ablated eosinophilia and ILC2 responses, and delayed recruitment and activation ofmacrophages to the M2 phenotype (expressing Arginase 1, Chil3, and RΕLM‐alpha) upon infection of MIF‐deficient mice; amacrophage deficit was also seen in wild-type BALB/c mice exposed to 4-IPP. Gene expression analysis of intestinal and lymph nodetissues from MIF-deficient and -sufficient infected mice indicated significantly reduced levels of Arl2bp, encoding a factor involved innuclear localization of STAT3. We further found that STAT3-deficient macrophages expressed less Arginase-1, and that mice lackingSTAT3 in the myeloid compartment (LysMCrexSTAT3fl/fl) were unable to reject a secondary infection with H. polygyrus. We thusconclude that in the context of a Type 2 infection, MIF plays a critical role in polarizing macrophages into the protectivealternatively-activated phenotype, and that STAT3 signaling may make a previously unrecognized contribution to immunity tohelminths.
Original languageEnglish
JournalFrontiers in immunology
Publication statusAccepted/In press - 23 Sep 2019

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