A Brugia malayi homolog of macrophage migration inhibitory factor reveals an important link between macrophages and eosinophil recruitment during nematode infection

Infections with the helminth parasite Brugia malayi share many key features with Th2-mediated allergic diseases, including recruitment of eosinophils. We have investigated the dynamics of inflammatory cell recruitment tinder type 2 cytokine conditions in mice infected with B. malayi. Among the cells recruited to the site of infection is a novel population of "alternatively activated" macrophages that ablate cell proliferation and enhance Th2 diff erentiation. By profiling gene expression in this macrophage population, we found a dramatic up-regulation of a recently described eosinophil chemotac tic factor, cosinophil chemotactic factor-L/Ym1, representing over 9% of cl ones randomly selected from a cDNA library. Because B. malayi is known to s ecrete homologs (Bm macrophage migration inhibitory factor (MIF)-1 and -2) of the human cytokine MIF, we chose to investigate the role this cytokine m imic may play in the development of the novel macrophage phenotype observed during infection. Strikingly, administration of soluble recombinant Bm-MIF -1 was able to reproduce the effects of live parasites, leading both to the upregulation of Ym1 by macrophages and a marked recruitment of eosinophils in vivo. Because activity of Bm-MIF-1 is dependent upon an amino-terminal proline, this residue was mutated to glycine; the resultant recombinant (Bi n-MIF-1G) was unable to induce Ym1 transcription in macrophages or to media te the recruitment of eosinophils. These data suggest that macrophages may provide a crucial link between helminth parasites, their active cytokine mi mics, and the recruitment of cosinophils In infection.