Topical Application of the PI3Kβ-Selective Small Molecule Inhibitor TGX-221 Is an Effective Treatment Option for Experimental Epidermolysis Bullosa Acquisita

Class I phosphoinositide 3-kinases (PI3K) have been implemented in pathogenesis of experimental epidermolysis bullosa acquisita (EBA), an autoimmune skin disease caused by type VII collagen (COL7) autoantibodies. Mechanistically, inhibition of specific PI3K isoforms, namely PI3Kβ or PI3Kδ, impaired...

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Published inFrontiers in medicine Vol. 8; p. 713312
Main Authors Zillikens, Hannah, Kasprick, Anika, Osterloh, Colin, Gross, Natalie, Radziewitz, Michael, Hass, Cindy, Hartmann, Veronika, Behnen-Härer, Martina, Ernst, Nancy, Boch, Katharina, Vidarsson, Gestur, Visser, Remco, Laskay, Tamás, Yu, Xinhua, Petersen, Frank, Ludwig, Ralf J., Bieber, Katja
Format Journal Article
LanguageEnglish
Published Frontiers Media S.A 07.09.2021
Subjects
bullous skin diseases
immune-complex induced autoimmunity
Medicine
neutrophils
PI3K
signaling
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Abstract Class I phosphoinositide 3-kinases (PI3K) have been implemented in pathogenesis of experimental epidermolysis bullosa acquisita (EBA), an autoimmune skin disease caused by type VII collagen (COL7) autoantibodies. Mechanistically, inhibition of specific PI3K isoforms, namely PI3Kβ or PI3Kδ, impaired immune complex (IC)-induced neutrophil activation, a key prerequisite for EBA pathogenesis. Data unrelated to EBA showed that neutrophil activation is also modulated by PI3Kα and γ, but their impact on the EBA has, so far, remained elusive. To address this and to identify potential therapeutic targets, we evaluated the impact of a panel of PI3K isoform-selective inhibitors (PI3Ki) on neutrophil function in vitro , and in pre-clinical EBA mouse models. We document that distinctive, and EBA pathogenesis-related activation-induced neutrophil in vitro functions depend on distinctive PI3K isoforms. When mice were treated with the different PI3Ki, selective blockade of PI3Kα (alpelisib), PI3Kγ (AS-604850), or PI3Kβ (TGX-221) impaired clinical disease manifestation. When applied topically, only TGX-221 impaired induction of experimental EBA. Ultimately, multiplex kinase activity profiling in the presence of disease-modifying PI3Ki identified unique signatures of different PI3K isoform-selective inhibitors on the kinome of IC-activated human neutrophils. Collectively, we here identify topical PI3Kβ inhibition as a potential therapeutic target for the treatment of EBA.
AbstractList Class I phosphoinositide 3-kinases (PI3K) have been implemented in pathogenesis of experimental epidermolysis bullosa acquisita (EBA), an autoimmune skin disease caused by type VII collagen (COL7) autoantibodies. Mechanistically, inhibition of specific PI3K isoforms, namely PI3Kβ or PI3Kδ, impaired immune complex (IC)-induced neutrophil activation, a key prerequisite for EBA pathogenesis. Data unrelated to EBA showed that neutrophil activation is also modulated by PI3Kα and γ, but their impact on the EBA has, so far, remained elusive. To address this and to identify potential therapeutic targets, we evaluated the impact of a panel of PI3K isoform-selective inhibitors (PI3Ki) on neutrophil function in vitro , and in pre-clinical EBA mouse models. We document that distinctive, and EBA pathogenesis-related activation-induced neutrophil in vitro functions depend on distinctive PI3K isoforms. When mice were treated with the different PI3Ki, selective blockade of PI3Kα (alpelisib), PI3Kγ (AS-604850), or PI3Kβ (TGX-221) impaired clinical disease manifestation. When applied topically, only TGX-221 impaired induction of experimental EBA. Ultimately, multiplex kinase activity profiling in the presence of disease-modifying PI3Ki identified unique signatures of different PI3K isoform-selective inhibitors on the kinome of IC-activated human neutrophils. Collectively, we here identify topical PI3Kβ inhibition as a potential therapeutic target for the treatment of EBA.
Class I phosphoinositide 3-kinases (PI3K) have been implemented in pathogenesis of experimental epidermolysis bullosa acquisita (EBA), an autoimmune skin disease caused by type VII collagen (COL7) autoantibodies. Mechanistically, inhibition of specific PI3K isoforms, namely PI3Kβ or PI3Kδ, impaired immune complex (IC)-induced neutrophil activation, a key prerequisite for EBA pathogenesis. Data unrelated to EBA showed that neutrophil activation is also modulated by PI3Kα and γ, but their impact on the EBA has, so far, remained elusive. To address this and to identify potential therapeutic targets, we evaluated the impact of a panel of PI3K isoform-selective inhibitors (PI3Ki) on neutrophil function in vitro, and in pre-clinical EBA mouse models. We document that distinctive, and EBA pathogenesis-related activation-induced neutrophil in vitro functions depend on distinctive PI3K isoforms. When mice were treated with the different PI3Ki, selective blockade of PI3Kα (alpelisib), PI3Kγ (AS-604850), or PI3Kβ (TGX-221) impaired clinical disease manifestation. When applied topically, only TGX-221 impaired induction of experimental EBA. Ultimately, multiplex kinase activity profiling in the presence of disease-modifying PI3Ki identified unique signatures of different PI3K isoform-selective inhibitors on the kinome of IC-activated human neutrophils. Collectively, we here identify topical PI3Kβ inhibition as a potential therapeutic target for the treatment of EBA.
Author Laskay, Tamás
Ludwig, Ralf J.
Yu, Xinhua
Hass, Cindy
Kasprick, Anika
Radziewitz, Michael
Bieber, Katja
Ernst, Nancy
Gross, Natalie
Behnen-Härer, Martina
Hartmann, Veronika
Visser, Remco
Petersen, Frank
Zillikens, Hannah
Osterloh, Colin
Boch, Katharina
Vidarsson, Gestur
AuthorAffiliation 2 Priority Area Asthma and Allergy, Research Center Borstel, Airway Research Center North, German Center for Lung Research , Borstel , Germany
1 Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck , Lübeck , Germany
3 Department for Infectious Diseases and Microbiology, University of Lübeck , Lübeck , Germany
4 Sanquin Research and Landsteiner Laboratory , Amsterdam , Netherlands
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Copyright Copyright © 2021 Zillikens, Kasprick, Osterloh, Gross, Radziewitz, Hass, Hartmann, Behnen-Härer, Ernst, Boch, Vidarsson, Visser, Laskay, Yu, Petersen, Ludwig and Bieber. 2021 Zillikens, Kasprick, Osterloh, Gross, Radziewitz, Hass, Hartmann, Behnen-Härer, Ernst, Boch, Vidarsson, Visser, Laskay, Yu, Petersen, Ludwig and Bieber
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Reviewed by: Hiroaki Iwata, Hokkaido University, Japan; Hiroshi Koga, Kurume University School of Medicine, Japan
This article was submitted to Dermatology, a section of the journal Frontiers in Medicine
Edited by: Oleg E. Akilov, University of Pittsburgh, United States
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Snippet Class I phosphoinositide 3-kinases (PI3K) have been implemented in pathogenesis of experimental epidermolysis bullosa acquisita (EBA), an autoimmune skin...
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SubjectTerms bullous skin diseases
immune-complex induced autoimmunity
Medicine
neutrophils
PI3K
signaling
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Title Topical Application of the PI3Kβ-Selective Small Molecule Inhibitor TGX-221 Is an Effective Treatment Option for Experimental Epidermolysis Bullosa Acquisita
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