TY - JOUR
T1 - Inhibition of Glucose Metabolism Abrogates the Effector Phase of Bullous Pemphigoid-Like Epidermolysis Bullosa Acquisita
AU - Schilf, Paul
AU - Schmitz, Marie
AU - Derenda-Hell, Aleksandra
AU - Thieme, Markus
AU - Bremer, Tabea
AU - Vaeth, Martin
AU - Zillikens, Detlef
AU - Sadik, Christian D.
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85103933868&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/37d265bc-096f-3dca-a30f-6231ca4d23ab/
U2 - 10.1016/j.jid.2021.01.014
DO - 10.1016/j.jid.2021.01.014
M3 - Journal articles
C2 - 33609554
AN - SCOPUS:85103933868
SN - 0022-202X
VL - 141
SP - 1646-1655.e3
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 7
ER -