title: Migration inhibitory factor (MIF) released by macrophages upon recognition of immune complexes is critical to inflammation in Arthus reaction.
abstract: Deposition of immune complexes (IC) triggers Fc gamma R-dependent inflammation, leading to tissue damage in rheumatoid arthritis, systemic lupus erythematous, immune glomerulonephritis, and several immune vasculitides. Evidences support a role for macrophage migration inhibitory factor (MIF) in a number of inflammatory diseases, but the triggering of its secretion and its physiopathological role upon IC deposition remain elusive. Herein, we show that human macrophages secreted MIF after IC recognition, which in turn controlled the secretion of TNF. Macrophages from Mif-/- mice produced smaller amounts of TNF when stimulated with IgG-opsonized erythrocytes than wild-type (WT) cells. Using passive reverse Arthus reaction in the peritoneum and lungs as a model for IC-induced inflammation, we demonstrated that Mif-/- mice had a milder response, observed by reduced neutrophil recruitment, vascular leakage, and secretion of TNF, MIP-2, and keratinocyte-derived chemokine compared with WT controls. Adoptive transfer of alveolar macrophages from WT to Mif-/- mice rescued pulmonary neutrophil recruitment and TNF production upon passive reverse Arthus reaction. Our study indicates that Arthus inflammatory reaction is largely dependent on MIF and poses macrophages as a source of the MIF released upon IC recognition. These results give experimental support to the proposition that blockade of MIF might constitute an adjunctive, therapeutic approach to IC disease.
authors.affiliation: Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro-UFRJ, Rio de Janeiro, Brazil. mbozza@micro.ufrj.br
authors.forename: Claudia N
authors.initials: CN
authors.lastname: Paiva
authors.forename: Rosa H
authors.initials: RH
authors.lastname: Arras
authors.forename: Elisabeth S
authors.initials: ES
authors.lastname: Magalhães
authors.forename: Letícia S
authors.initials: LS
authors.lastname: Alves
authors.forename: Luiz Paulo
authors.initials: LP
authors.lastname: Lessa
authors.forename: Maria Helena
authors.initials: MH
authors.lastname: Silva
authors.forename: Regina
authors.initials: R
authors.lastname: Ejzemberg
authors.forename: Cláudio
authors.initials: C
authors.lastname: Canetti
authors.forename: Marcelo T
authors.initials: MT
authors.lastname: Bozza
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D001183:Arthus Reaction / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D019746:Intramolecular Oxidoreductases / Q000276:immunology*; D008168:Lung / Q000276:immunology; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D017452:Receptors, IgG / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000096:biosynthesis*
chemical_list: D000936:Antigen-Antibody Complex; D008263:Macrophage Migration-Inhibitory Factors; D017452:Receptors, IgG; D048069:Tumor Necrosis Factors; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human