Cross-Talk between Macrophage Migration Inhibitory Factor and Eotaxin in Allergic Eosinophil Activation Forms Leukotriene C₄–Synthesizing Lipid Bodies

Abstract

Recent studies have demonstrated an essential and nonredundant role for macrophage migration inhibitory factor (MIF) in asthma pathogenesis. Here we investigate the mechanisms involved in MIF-induced eosinophil activation. By using a model of allergic pulmonary inflammation, we observed that allergen challenge-elicited eosinophil influx, lipid body (also known as lipid droplets) biogenesis, and leukotriene (LT) C₄ synthesis are markedly reduced in Mif(-/-) compared with wild-type mice. Likewise, in vivo administration of MIF induced formation of new lipid bodies within eosinophils recruited to the inflammatory reaction site that corresponded to the intracellular compartment of increased LTC₄ synthesis. MIF-mediated eosinophil activation was at least in part due to a direct effect on eosinophils, because MIF was able to elicit lipid body assembly within human eosinophils in vitro, a phenomenon that was blocked by neutralization of the MIF receptor, CD74. MIF-induced eosinophil lipid body biogenesis, both in vivo and in vitro, was dependent on the cooperation of MIF and eotaxin acting in a positive-feedback loop, because anti-eotaxin and anti-CCR3 antibodies inhibit MIF-elicited lipid body formation, whereas eotaxin-induced lipid body formation is affected by anti-CD74 and MIF expression deficiency. Therefore, allergy-elicited inflammatory MIF acts in concert with eotaxin as a key activator of eosinophils to form LTC₄-synthesizing lipid bodies via cross-talk between CD74 and CCR3. Due to the effect of MIF on eosinophils, strategies that inhibit MIF activity might be of therapeutic value in controlling allergic inflammation.

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

“…Nevertheless, in addition to the well-established Th2 background, these molecules apparently were not modulated by MIF, found in remarkably increased amounts in EoE samples. Although MIF has been shown to induce IL-5, IL-13 and eotaxin-3 in the lungs of allergic mice and eotaxin-3 by human eosinophils 15,17 , we also observed that MIF constitutes a critical survival factor for eosinophils, regardless of IL-5 or IL-13 levels 16 . Therefore, in this study we hypothesize that MIF may act in a relative independence of IL-5, IL-13, or eotaxin-3, through its effects on eosinophil recruitment and survival, suggesting a role for MIF as a key component of both Th2 and innate immune response circuits involved in the control of inflammation in EoE.…”

“…Considering that in this study MIF was present mostly in eosinophils within the esophageal mucosa, it is conceivable that MIF may not constitute a primary trigger in EoE, but still emerges as a key element in the effector arm of EoE associated inflammation. Because of the ability of eosinophils to produce MIF 13,17 , it is also likely that effects observed in vivo might be a result of an autocrine/paracrine action of MIF released by eosinophil precursors in EoE.…”

“…Activated Th2 cells have increased MIF mRNA and protein, while eosinophils have the pre-formed protein and are able to secrete high quantities of MIF upon stimulation 13,14 . MIF also profoundly affects eosinophil physiology promoting eosinophil differentiation, activation, migration and survival 15-17 . In mouse models of asthma and allergic rhinitis the lack of MIF causes an almost complete abrogation of the cardinal signs of the disease including mucus secretion, eosinophilic inflammation and airway hyper-responsiveness 15,18,19 .…”

Exploratory Investigation of Early Biomarkers for Chronic Fatigue in Prostate Cancer Patients Following Radiation Therapy

“…The novel correlation between fatigue intensification and eosinophil counts found in this study may be attributable to the increased concentrations of MIF, which has been shown to induce eosinophil infiltration and activation 47, 48 . Interestingly, eosinophils are a major source of cytokines and have been shown to release up to 35 different cytokines 49 .…”

Lipid droplets in leukocytes: Organelles linked to inflammatory responses

“…LDs biogenesis is well documented both in vitro and in vivo in response to inflammatory stimuli and diseases (reviewed in [1, 2, 15]). For instance, increased LDs numbers are observed during acute respiratory distress syndrome [16] and allergic inflammation [17] in humans. Interestingly, eosinophils from patients with hypereosinophlic syndrome (HES) are naturally activated and show both increased numbers of LDs and enhanced leukotriene C 4 (LTC 4 ) production [18, 19].…”