Dapsone Suppresses Disease in Preclinical Murine Models of Pemphigoid Diseases.

Epidermolysis bullosa acquisita and mucous membrane pemphigoid are autoimmune blistering diseases characterized by mucocutaneous blisters elicited by an autoantibody-mediated immune response against specific proteins of the epidermal basement membrane. The antibiotic dapsone is frequently used to treat both diseases, but its therapeutic effectiveness is uncertain, and its mode of action in these diseases is largely unknown. We evaluated the effect of dapsone in antibody transfer mouse models of epidermolysis bullosa acquisita and mucous membrane pemphigoid, which do not allow the drawing of conclusions on clinical treatment regimens but can be instrumental to partially uncover the mode(s) of action of dapsone in these diseases. Dapsone significantly mitigated inflammation in both models, reducing the recruitment of neutrophils into the skin and disrupting their release of leukotriene B4 (LTB4) and ROS in response to immune complexes. LTB4 has been implicated in numerous diseases, but effective LTB4 inhibitors for clinical use are not available. Our findings indicate that the mode of action of dapsone in these models may be based on the inhibition of LTB4 and ROS release from neutrophils. Moreover, they encourage testing the use of dapsone as an effective, albeit nonspecific, inhibitor of LTB4 biosynthesis in other LTB4-driven diseases.

Inhibition of Glucose Metabolism Abrogates the Effector Phase of Bullous Pemphigoid-Like Epidermolysis Bullosa Acquisita.

Bullous pemphigoid-like epidermolysis bullosa acquisita (EBA) is an autoantibody-driven, granulocyte-mediated skin disease. The role of cellular metabolism and its potential as a therapeutic target in EBA are unknown. We investigated the effect of 2-deoxy-D-glucose and metformin in the antibody transfer model of EBA. Both metformin and 2-deoxy-D-glucose attenuated disease in this model. Subsequently, we demonstrate that the stimulation of neutrophils by immune complexes increases the rate of aerobic glycolysis and that this increase is required to induce the release of leukotriene B4 and ROS critical for EBA. Accordingly, 2-deoxy-D-glucose as an inhibitor of the glycolytic enzymes hexokinase and phosphoglucose isomerase and heptelidic acid, an inhibitor of glyceraldehyde-3-phosphate dehydrogenase, blunted this neutrophil response. Decreasing oxidative phosphorylation, metformin also inhibited this neutrophil response but only when applied in suprapharmacological doses, rendering a direct effect of metformin on neutrophils in vivo unlikely. Considering that the oxidative phosphorylation inhibitor oligomycin likewise inhibits these neutrophil responses and that immune complex stimulation does not alter the rate of oxidative phosphorylation, these results, however, suggest that intact mitochondria are necessary for neutrophil responses. Collectively, we highlight 2-deoxy-D-glucose and metformin as potential drugs and both glycolysis and oxidative phosphorylation in neutrophils as promising therapeutic targets in EBA.