Paiva Claudia N, Arras Rosa H, Magalhães Elisabeth S, Alves Letícia S, Lessa Luiz Paulo, Silva Maria Helena, Ejzemberg Regina, Canetti Cláudio, Bozza Marcelo T
Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro-UFRJ, Rio de Janeiro, Brazil.
J Leukoc Biol. 2009 May;85(5):855-61. doi: 10.1189/jlb.0108009. Epub 2009 Feb 2.
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.
免疫复合物（IC）的沉积引发FcγR依赖性炎症，导致类风湿性关节炎、系统性红斑狼疮、免疫性肾小球肾炎及多种免疫性血管炎中的组织损伤。有证据支持巨噬细胞移动抑制因子（MIF）在多种炎症性疾病中发挥作用，但IC沉积时其分泌的触发因素及其生理病理作用仍不清楚。在此，我们表明人类巨噬细胞在识别IC后分泌MIF，进而控制TNF的分泌。与野生型（WT）细胞相比，用IgG调理的红细胞刺激时，Mif-/-小鼠的巨噬细胞产生的TNF量较少。使用腹膜和肺部的被动反向阿瑟斯反应作为IC诱导炎症的模型，我们证明与WT对照相比，Mif-/-小鼠的反应较轻，表现为中性粒细胞募集减少、血管渗漏以及TNF、MIP-2和角质形成细胞衍生趋化因子的分泌减少。将WT小鼠的肺泡巨噬细胞过继转移到Mif-/-小鼠可挽救被动反向阿瑟斯反应时肺部的中性粒细胞募集和TNF产生。我们的研究表明阿瑟斯炎症反应在很大程度上依赖于MIF，并表明巨噬细胞是IC识别后释放的MIF的来源。这些结果为MIF阻断可能构成IC疾病辅助治疗方法的观点提供了实验支持。
