Local steroid activation is a critical mediator of the anti-inflammatory actions of therapeutic glucocorticoids

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@article{678a66d722db4828b5464b4170bb87da,
title = "Local steroid activation is a critical mediator of the anti-inflammatory actions of therapeutic glucocorticoids",
abstract = "Objectives The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a well-characterised role in the metabolism and activation of endogenous glucocorticoids (GCs). However, despite its potent upregulation at sites of inflammation, its role in peripheral metabolism and action of therapeutic GCs remains poorly understood. We investigated the contribution of 11β-HSD1 to the anti-inflammatory properties of the active GC corticosterone, administered at therapeutic doses in murine models of polyarthritis.Methods Using the tumour necrosis factor-tg and K/BxN serum-induced models of polyarthritis, we examined the anti-inflammatory properties of oral administration of corticosterone in animals with global, myeloid and mesenchymal targeted transgenic deletion of 11β-HSD1. Disease activity and joint inflammation were scored daily. Joint destruction and measures of local and systemic inflammation were determined by histology, micro-CT, quantitative RT-PCR, fluorescence activated cell sorting and ELISA.Results Global deletion of 11β-HSD1 resulted in a profound GC resistance in animals receiving corticosterone, characterised by persistent synovitis, joint destruction and inflammatory leucocyte infiltration. This was partially reproduced with myeloid, but not mesenchymal 11β-HSD1 deletion, where paracrine GC signalling between cell populations was shown to overcome targeted deletion of 11β-HSD1.Conclusions We identify an entirely novel component of therapeutic GC action, whereby following their systemic metabolism, they require peripheral reactivation and amplification by 11β-HSD1 at sites of inflammation to deliver their anti-inflammatory therapeutic effects. This study provides a novel mechanistic understanding of the anti-inflammatory properties of therapeutic GCs and their targeting to sites of inflammation in polyarthritis.",
keywords = "arthritis, experimental, glucocorticoids, inflammation, synovitis",
author = "Chloe Fenton and Claire Martin and Rachel Jones and Adam Croft and Joana Campos and Amy Naylor and Angela Taylor and Myriam Chimen and Mark Cooper and Gareth Lavery and Karim Raza and Rowan Hardy",
note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.",
year = "2021",
month = feb,
doi = "10.1136/annrheumdis-2020-218493",
language = "English",
volume = "80",
pages = "250--260",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
publisher = "BMJ Publishing Group",
number = "2",

}

RIS

TY - JOUR

T1 - Local steroid activation is a critical mediator of the anti-inflammatory actions of therapeutic glucocorticoids

AU - Fenton, Chloe

AU - Martin, Claire

AU - Jones, Rachel

AU - Croft, Adam

AU - Campos, Joana

AU - Naylor, Amy

AU - Taylor, Angela

AU - Chimen, Myriam

AU - Cooper, Mark

AU - Lavery, Gareth

AU - Raza, Karim

AU - Hardy, Rowan

N1 - Publisher Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

PY - 2021/2

Y1 - 2021/2

N2 - Objectives The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a well-characterised role in the metabolism and activation of endogenous glucocorticoids (GCs). However, despite its potent upregulation at sites of inflammation, its role in peripheral metabolism and action of therapeutic GCs remains poorly understood. We investigated the contribution of 11β-HSD1 to the anti-inflammatory properties of the active GC corticosterone, administered at therapeutic doses in murine models of polyarthritis.Methods Using the tumour necrosis factor-tg and K/BxN serum-induced models of polyarthritis, we examined the anti-inflammatory properties of oral administration of corticosterone in animals with global, myeloid and mesenchymal targeted transgenic deletion of 11β-HSD1. Disease activity and joint inflammation were scored daily. Joint destruction and measures of local and systemic inflammation were determined by histology, micro-CT, quantitative RT-PCR, fluorescence activated cell sorting and ELISA.Results Global deletion of 11β-HSD1 resulted in a profound GC resistance in animals receiving corticosterone, characterised by persistent synovitis, joint destruction and inflammatory leucocyte infiltration. This was partially reproduced with myeloid, but not mesenchymal 11β-HSD1 deletion, where paracrine GC signalling between cell populations was shown to overcome targeted deletion of 11β-HSD1.Conclusions We identify an entirely novel component of therapeutic GC action, whereby following their systemic metabolism, they require peripheral reactivation and amplification by 11β-HSD1 at sites of inflammation to deliver their anti-inflammatory therapeutic effects. This study provides a novel mechanistic understanding of the anti-inflammatory properties of therapeutic GCs and their targeting to sites of inflammation in polyarthritis.

AB - Objectives The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a well-characterised role in the metabolism and activation of endogenous glucocorticoids (GCs). However, despite its potent upregulation at sites of inflammation, its role in peripheral metabolism and action of therapeutic GCs remains poorly understood. We investigated the contribution of 11β-HSD1 to the anti-inflammatory properties of the active GC corticosterone, administered at therapeutic doses in murine models of polyarthritis.Methods Using the tumour necrosis factor-tg and K/BxN serum-induced models of polyarthritis, we examined the anti-inflammatory properties of oral administration of corticosterone in animals with global, myeloid and mesenchymal targeted transgenic deletion of 11β-HSD1. Disease activity and joint inflammation were scored daily. Joint destruction and measures of local and systemic inflammation were determined by histology, micro-CT, quantitative RT-PCR, fluorescence activated cell sorting and ELISA.Results Global deletion of 11β-HSD1 resulted in a profound GC resistance in animals receiving corticosterone, characterised by persistent synovitis, joint destruction and inflammatory leucocyte infiltration. This was partially reproduced with myeloid, but not mesenchymal 11β-HSD1 deletion, where paracrine GC signalling between cell populations was shown to overcome targeted deletion of 11β-HSD1.Conclusions We identify an entirely novel component of therapeutic GC action, whereby following their systemic metabolism, they require peripheral reactivation and amplification by 11β-HSD1 at sites of inflammation to deliver their anti-inflammatory therapeutic effects. This study provides a novel mechanistic understanding of the anti-inflammatory properties of therapeutic GCs and their targeting to sites of inflammation in polyarthritis.

KW - arthritis

KW - experimental

KW - glucocorticoids

KW - inflammation

KW - synovitis

UR - http://www.scopus.com/inward/record.url?scp=85096000429&partnerID=8YFLogxK

U2 - 10.1136/annrheumdis-2020-218493

DO - 10.1136/annrheumdis-2020-218493

M3 - Article

VL - 80

SP - 250

EP - 260

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

IS - 2

ER -