ERK5 is required for neutrophil-mediated ROS release and essential in epidermolysis bullosa acquisita

Draeger, S.; Schlotfeldt, M.; Voss, L.; Johannisson, S.; Radziewitz, M.; Osterloh, C.; Gross, N.; Kamaguchi, M.; Schneider, A.-K.; Vidarsson, G.; Visser, R.; Petersen, F.; Yu, X.; Recke, A.; Ernst, N.; Lux, A.; Bieber, K.

doi:10.1101/2025.11.12.688045

bioRxiv · 10.1101/2025.11.12.688045

ERK5 is required for neutrophil-mediated ROS release and essential in epidermolysis bullosa acquisita

Draeger, S.·Schlotfeldt, M.·Voss, L.·Johannisson, S.·Radziewitz, M.·Osterloh, C.·Gross, N.·Kamaguchi, M.·Schneider, A.-K.·Vidarsson, G.·Visser, R.·Petersen, F.·Yu, X.·Recke, A.·Ernst, N.·Lux, A.·Bieber, K.

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Abstract

Neutrophils are key effector cells in antibody-mediated autoimmune diseases, contributing to inflammation via the release of reactive oxygen species (ROS). Extracellular signal-regulated kinase 5 (ERK5), a member of the MAPK family, is expressed in neutrophils but its role in autoimmune disease pathogenesis remains unclear. We investigated the functional relevance of ERK5 in antibody-mediated autoimmune diseases by comparing neutrophil-dependent (epidermolysis bullosa acquisita, EBA; serum transfer arthritis, STA) and neutrophil-independent (immune thrombocytopenia, ITP) murine models using the small-molecule ERK5 inhibitor XMD8-92. In vitro, pharmacological ERK5 inhibition specifically reduced neutrophil ROS release and CD62L shedding without affecting adhesion, chemotaxis, or CD18 expression. No major effects on viability were observed. In vivo, ERK5 inhibition with XMD8-92 significantly ameliorated antibody transfer-induced EBA, supporting a critical role of neutrophil-derived ROS in disease pathogenesis. In STA and ITP, ERK5 inhibition did not affect clinical outcomes. Together, these findings highlight ERK5 as a regulator of neutrophil ROS release and a potential therapeutic target in ROS-driven autoimmune diseases such as EBA.

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Draeger, S., Schlotfeldt, M., Voss, L., Johannisson, S., Radziewitz, M., Osterloh, C., Gross, N., Kamaguchi, M., Schneider, A.-K., Vidarsson, G., Visser, R., Petersen, F., Yu, X., Recke, A., Ernst, N., Lux, A., Bieber, K.. 2025-11-13. ERK5 is required for neutrophil-mediated ROS release and essential in epidermolysis bullosa acquisita. https://doi.org/10.1101/2025.11.12.688045

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