RESUMO
Autoimmunity leads to the activation of innate effector pathways, proinflammatory cytokine production, and end-organ injury. Macrophage migration inhibitory factor (MIF) is an upstream activator of the innate response that mediates the recruitment and retention of monocytes via CD74 and associated chemokine receptors, and it has a role in the maintenance of B lymphocytes. High-expression MIF alleles also are associated with end-organ damage in different autoimmune diseases. We assessed the therapeutic efficacy of (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), an orally bioavailable MIF antagonist, in two distinct models of systemic lupus erythematosus: the NZB/NZW F1 and the MRL/lpr mouse strains. ISO-1, like anti-MIF, inhibited the interaction between MIF and its receptor, CD74, and in each model of disease, it reduced functional and histological indices of glomerulonephritis, CD74(+) and CXCR4(+) leukocyte recruitment, and proinflammatory cytokine and chemokine expression. Neither autoantibody production nor T and B cell activation were significantly affected, pointing to the specificity of MIF antagonism in reducing excessive proinflammatory responses. These data highlight the feasibility of targeting the MIF-MIF receptor interaction by small-molecule antagonism and support the therapeutic value of downregulating MIF-dependent pathways of tissue damage in systemic lupus erythematosus.
Assuntos
Predisposição Genética para Doença , Glomerulonefrite/prevenção & controle , Oxirredutases Intramoleculares/antagonistas & inibidores , Isoxazóis/uso terapêutico , Lúpus Eritematoso Sistêmico/prevenção & controle , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Inibição de Migração Celular/efeitos dos fármacos , Inibição de Migração Celular/imunologia , Feminino , Perfilação da Expressão Gênica , Glomerulonefrite/genética , Glomerulonefrite/imunologia , Humanos , Oxirredutases Intramoleculares/biossíntese , Isoxazóis/administração & dosagem , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Fatores Inibidores da Migração de Macrófagos/biossíntese , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Endogâmicos NZB , Camundongos Knockout , Dados de Sequência Molecular , Distribuição Aleatória , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/biossínteseRESUMO
IMPORTANCE OF THE FIELD: Autoimmune inflammatory diseases occur commonly in developed countries. The treatment of these diseases is usually non-curative and is aimed at suppressing inflammatory end-organ damage. Macrophage migration inhibitory factor (MIF) is a multipotent cytokine that has been implicated in the pathogenesis of numerous autoimmune inflammatory disorders. The selective targeting of MIF with either anti-MIF antibody or specific MIF antagonists may offer new therapeutic avenues for these diseases. AREAS COVERED IN THIS REVIEW: Our aim is to discuss MIF-directed therapies as a novel therapeutic approach. The review covers literature from the past 10 years. WHAT THE READER WILL GAIN: MIF inhibition has been shown to be efficacious in many experimental and pre-clinical studies of autoimmune inflammatory diseases. The close regulatory relationship between MIF and glucocorticoids makes therapeutic antagonism of MIF a potential steroid-sparing therapy in patients with refractory autoimmune diseases. TAKE HOME MESSAGE: We expect that MIF antagonism by either small-molecule- or antibody-based approaches will find wide application in the treatment of autoimmune inflammatory diseases. Such therapy also may be informed by the MIF genotype of affected patients.