Migration inhibitory factor (MIF) released by macrophages upon recognition of immune complexes is critical to inflammation in Arthus reaction

Deposition of immune complexes (IC) triggers FcR-dependent inflammation, leading to tissue damage in rheumatoid arthritis, systemic lu- pus erythematous, immune glomerulonephritis, and several immune vasculitides. Evidences sup- port a role for macrophage migration inhibitory factor (MIF) in a number of inflammatory diseases, but the triggering of its secretion and its physio- pathological role upon IC deposition remain elu- sive. 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 erythro- cytes than wild-type (WT) cells. Using passive re- verse Arthus reaction in the peritoneum and lungs as a model for IC-induced inflammation, we dem- onstrated that Mif/ mice had a milder response, observed by reduced neutrophil recruitment, vas- cular leakage, and secretion of TNF, MIP-2, and keratinocyte-derived chemokine compared with WT controls. Adoptive transfer of alveolar macro- phages from WT to Mif/ mice rescued pulmo- nary 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 recogni- tion. These results give experimental support to the proposition that blockade of MIF might consti- tute an adjunctive, therapeutic approach to IC disease. J. Leukoc. Biol. 85: 000-000; 2009.