Membrane damage by MBP-1 is mediated by pore formation and amplified by mtDNA
Lea Gigon,
Philipp Müller,
Beat Haenni,
Ioan Iacovache,
Maruša Barbo,
Gordana Gosheva,
Shida Yousefi,
Alice Soragni,
Christoph von Ballmoos,
Benoît Zuber,
Hans-Uwe Simon
Affiliations
Lea Gigon
Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland
Philipp Müller
Department of Chemistry, Biochemistry, and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland
Beat Haenni
Institute of Anatomy, University of Bern, 3012 Bern, Switzerland
Ioan Iacovache
Institute of Anatomy, University of Bern, 3012 Bern, Switzerland
Maruša Barbo
Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland; Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
Gordana Gosheva
Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland; Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
Shida Yousefi
Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland
Alice Soragni
Department of Orthopedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Christoph von Ballmoos
Department of Chemistry, Biochemistry, and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland
Benoît Zuber
Institute of Anatomy, University of Bern, 3012 Bern, Switzerland
Hans-Uwe Simon
Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland; Institute of Biochemistry, Brandenburg Medical School, 16816 Neuruppin, Germany; Corresponding author
Summary: Eosinophils play a crucial role in host defense while also contributing to immunopathology through the release of inflammatory mediators. Characterized by distinctive cytoplasmic granules, eosinophils securely store and rapidly release various proteins exhibiting high toxicity upon extracellular release. Among these, major basic protein 1 (MBP-1) emerges as an important mediator in eosinophil function against pathogens and in eosinophil-associated diseases. While MBP-1 targets both microorganisms and host cells, its precise mechanism remains elusive. We demonstrate that formation of small pores by MBP-1 in lipid bilayers induces membrane permeabilization and disrupts potassium balance. Additionally, we reveal that mitochondrial DNA (mtDNA) present in eosinophil extracellular traps (EETs) amplifies MBP-1 toxic effects, underscoring the pivotal role of mtDNA in EETs. Furthermore, we present evidence indicating that absence of CpG methylation in mtDNA contributes to the regulation of MBP-1-mediated toxicity. Taken together, our data suggest that the mtDNA scaffold within extracellular traps promotes MBP-1 toxicity.
