Macrophage migration inhibitory factor promotes eosinophil accumulation and tissue remodeling in eosinophilic esophagitis

Abstract

Macrophage migration inhibitory factor (MIF) is involved in eosinophil biology and in Type 2 inflammation, contributing to allergic and helminthic diseases. We hypothesized that MIF participates in the pathogenesis of eosinophilic esophagitis (EoE), an allergic condition characterized by esophageal eosinophilic inflammation. MIF is highly expressed in esophageal mucosa of patients with EoE, compared to gastro-esophageal reflux disease and control patients, where it co-localizes predominantly with eosinophils. In vitro, recombinant MIF promotes human eosinophil chemotaxis, while MIF antagonist and CXCR4 antagonist, AMD3100, revert this effect. In a model of EoE induced by ovalbumin, Mif deficient mice have reduced inflammation and collagen deposition compared to wild type mice. Importantly, treatment of wild type mice with anti-MIF or with AMD3100 during the challenge phase prevents accumulation of eosinophils and tissue remodeling. Conversely, recombinant MIF promoted tissue eosinophil inflammation in allergic mice. Together, these results implicate MIF in the pathogenesis of esophageal inflammation and suggest that targeting MIF might represent a novel therapy for EoE.

Macrophage migration inhibitory factor drives neutrophil accumulation by facilitating IL-1β production in a murine model of acute gout

“…Here, MIF increased the levels of IL-1b and CXCL1 in the inflamed joints. This is consistent with the ability of MIF to induce proinflammatory mediators in other conditions [29,[40][41][42]. More importantly, blockade of MIF action with ISO-1 was associated with inhibition of IL-1b levels in response to injection of MSU crystals.…”

“…Different studies have shown that the absence of MIF or its blockade by antibodies reduced the recruitment of leukocytes under inflammatory conditions [29,30,33], including autoimmune arthritis [34][35][36]. It was demonstrated previously that the small molecule ISO-1 inhibits MIF tautomerase activity, suppressing its proinflammatory activities [37].…”

“…*P , 0.05 versus saline group; #P , 0.05 versus vehicle group (mice only challenged with MSU crystals; ANOVA followed by Newman-Keuls posttest). eosinophils [19,[27][28][29][30]. MIF is considered to play a role in acute and chronic immunoinflammatory conditions, including rheumatoid arthritis, atherosclerosis, and lupus erythematosus [31].…”

Plasma levels of innate immune mediators are associated with liver fibrosis in low parasite burden Schistosoma mansoni‐infected individuals

“…Migration inhibitory factor production was previously associated with macrophage and lymphocyte activation in Th1‐ and Th2‐mediated chronic inflammatory diseases . In some Th2‐inflammatory diseases, MIF promotes eosinophil migration and activation, contributing with the disease severity . In S. mansoni ‐infected mice, there are increased MIF production during granuloma formation .…”

“…Moreover, MIF‐deficient mice showed reduced eosinophil recruitment in Schistosoma ‐induced liver granulomas, which were smaller and presented less cellularity than the granulomas formed by their wild‐type counterparts . A pro‐fibrotic effect of MIF was demonstrated in experimental models of OVA‐induced eosinophilic esophagitis, ConA‐induced hepatic fibrosis and OVA‐induced asthma . In the carbon tetrachloride (CCl4)‐induced liver fibrosis model, female MIF‐deficient mice showed reduced leucocyte recruitment, especially inflammatory macrophages, a significant reduction in HSC activation and synthesis of collagen 1α1 mRNA during the initial response .…”