Granzyme B inhibition reduces disease severity in autoimmune blistering diseases

Sho Hiroyasu; Matthew R. Zeglinski; Hongyan Zhao; Megan A. Pawluk; Christopher T. Turner; Anika Kasprick; Chiharu Tateishi; Wataru Nishie; Angela Burleigh; Peter A. Lennox; Nancy Van Laeken; Nick J. Carr; Frank Petersen; Richard I. Crawford; Hiroshi Shimizu; Daisuke Tsuruta; Ralf J. Ludwig; David J. Granville

doi:10.1038/s41467-020-20604-3

Granzyme B inhibition reduces disease severity in autoimmune blistering diseases

Sho Hiroyasu, Matthew R. Zeglinski, Hongyan Zhao, Megan A. Pawluk, Christopher T. Turner, Anika Kasprick, Chiharu Tateishi, Wataru Nishie, Angela Burleigh, Peter A. Lennox, Nancy Van Laeken, Nick J. Carr, Frank Petersen, Richard I. Crawford, Hiroshi Shimizu, Daisuke Tsuruta, Ralf J. Ludwig, David J. Granville^*

^*Korrespondierende/r Autor/-in für diese Arbeit

88 Zitate (Scopus)

Abstract

Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.

Originalsprache	Englisch
Aufsatznummer	302
Zeitschrift	Nature Communications
Jahrgang	12
Ausgabenummer	1
Seiten (von - bis)	302
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-020-20604-3
Publikationsstatus	Veröffentlicht - 01.12.2021

Fördermittel

We express our thanks to Dr. Karen Jung and Aoi Hiroyasu from the Granville laboratory, ICORD, UBC, and Tatjana Bozin from the Centre for Heart Lung Innovation, St. Paul’s Hospital, UBC, for their assistance with manuscript editing, experiments, and animal husbandry, respectively. This research was supported by funding from the Canadian Institutes for Health Research (CIHR) (D.J.G.) and the Michael Smith Foundation for Health Research (MSFHR) (D.J.G.). S.H. and C.T.T. are supported by CIHR Post-doctoral Fellowships. M.R.Z. is supported by a CIHR Post-doctoral Fellowship and a MSFHR Post-doctoral Fellowship.

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen
SDG 6 – Sauberes Wasser und sanitäre Einrichtungen

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)
Zentren: Center for Research on Inflammation of the Skin (CRIS)

DFG-Fachsystematik

2.21-05 Immunologie
2.22-19 Dermatologie

Dokumente

10.1038/s41467-020-20604-3

Weitere Links

KFO 303: Pemphigoid Diseases - Molecular Pathways and their Therapeutic Potential
Sadik, C. (Sprecher*in), Zillikens, D. (Sprecher*in), Ibrahim, S. (Projektleiter*in (PI)), Baines, J. F. (Projektleiter*in (PI)), Schmidt, E. (Projektleiter*in (PI)), Köhl, J. (Projektleiter*in (PI)), Ehlers, M. (Projektleiter*in (PI)), Hirose, M. (Projektleiter*in (PI)), König, P. (Projektleiter*in (PI)), Ludwig, R. (Projektleiter*in (PI)), Manz, R. (Projektleiter*in (PI)), Schwaninger, M. (Projektleiter*in (PI)), Beek, N. (Projektleiter*in (PI)), Erdmann, J. (Projektleiter*in (PI)), König, I. R. (Projektleiter*in (PI)), Verschoor, A. (Projektleiter*in (PI)), Karsten, C. (Projektleiter*in (PI)), Bieber, K. (Projektleiter*in (PI)) & Busch, H. S. (Projektleiter*in (PI))
01.04.15 → 31.12.23
Projekt: DFG Verbundprojekte › DFG Klinische Forschungsgruppen (KFO)

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Hiroyasu, S., Zeglinski, M. R., Zhao, H., Pawluk, M. A., Turner, C. T., Kasprick, A., Tateishi, C., Nishie, W., Burleigh, A., Lennox, P. A., Van Laeken, N., Carr, N. J., Petersen, F., Crawford, R. I., Shimizu, H., Tsuruta, D., Ludwig, R. J., & Granville, D. J. (2021). Granzyme B inhibition reduces disease severity in autoimmune blistering diseases. Nature Communications, 12(1), 302. Artikel 302. https://doi.org/10.1038/s41467-020-20604-3

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title = "Granzyme B inhibition reduces disease severity in autoimmune blistering diseases",

abstract = "Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.",

author = "Sho Hiroyasu and Zeglinski, \{Matthew R.\} and Hongyan Zhao and Pawluk, \{Megan A.\} and Turner, \{Christopher T.\} and Anika Kasprick and Chiharu Tateishi and Wataru Nishie and Angela Burleigh and Lennox, \{Peter A.\} and \{Van Laeken\}, Nancy and Carr, \{Nick J.\} and Frank Petersen and Crawford, \{Richard I.\} and Hiroshi Shimizu and Daisuke Tsuruta and Ludwig, \{Ralf J.\} and Granville, \{David J.\}",

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doi = "10.1038/s41467-020-20604-3",

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Hiroyasu, S, Zeglinski, MR, Zhao, H, Pawluk, MA, Turner, CT, Kasprick, A, Tateishi, C, Nishie, W, Burleigh, A, Lennox, PA, Van Laeken, N, Carr, NJ, Petersen, F, Crawford, RI, Shimizu, H, Tsuruta, D, Ludwig, RJ & Granville, DJ 2021, 'Granzyme B inhibition reduces disease severity in autoimmune blistering diseases', Nature Communications, Jg. 12, Nr. 1, 302, S. 302. https://doi.org/10.1038/s41467-020-20604-3

TY - JOUR

T1 - Granzyme B inhibition reduces disease severity in autoimmune blistering diseases

AU - Hiroyasu, Sho

AU - Zeglinski, Matthew R.

AU - Zhao, Hongyan

AU - Pawluk, Megan A.

AU - Turner, Christopher T.

AU - Kasprick, Anika

AU - Tateishi, Chiharu

AU - Nishie, Wataru

AU - Burleigh, Angela

AU - Lennox, Peter A.

AU - Van Laeken, Nancy

AU - Carr, Nick J.

AU - Petersen, Frank

AU - Crawford, Richard I.

AU - Shimizu, Hiroshi

AU - Tsuruta, Daisuke

AU - Ludwig, Ralf J.

AU - Granville, David J.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.

AB - Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.

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Granzyme B inhibition reduces disease severity in autoimmune blistering diseases

Abstract

Fördermittel

UN SDGs

Strategische Forschungsbereiche und Zentren

DFG-Fachsystematik

Dokumente

Weitere Links

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Projekte

KFO 303: Pemphigoid Diseases - Molecular Pathways and their Therapeutic Potential

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