Cross-talk between macrophage migration inhibitory factor and eotaxin in allergic eosinophil activation forms leukotriene C₄-synthesizing lipid bodies.
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.
Vieira-de-Abreu
Adriana
A
Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, RJ, 21045-900 Brazil.
Calheiros
Andrea S
AS
Mesquita-Santos
Fabio P
FP
Magalhães
Elisabeth S
ES
Mourão-Sá
Diego
D
Castro-Faria-Neto
Hugo C
HC
Bozza
Marcelo T
MT
Bandeira-Melo
Christianne
C
Bozza
Patricia T
PT
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D054413:Chemokine CCL11 / Q000378:metabolism*; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000150:complications / Q000276:immunology* / Q000473:pathology; D002479:Inclusion Bodies / Q000187:drug effects / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D017997:Leukotriene C4 / Q000096:biosynthesis*; D050356:Lipid Metabolism / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D051379:Mice; D018448:Models, Immunological; D011014:Pneumonia / Q000150:complications / Q000276:immunology / Q000473:pathology
D000944:Antigens, Differentiation, B-Lymphocyte; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; C045084:invariant chain; D017997:Leukotriene C4; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse