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11β-HSD1 suppresses cardiac fibroblast CXCL2, CXCL5 and neutrophil recruitment to the heart post MI

Lookup NU author(s): Professor Brian Walker

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2017 The authors.We have previously demonstrated that neutrophil recruitment to the heart following myocardial infarction (MI) is enhanced in mice lacking 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that regenerates active glucocorticoid within cells from intrinsically inert metabolites. The present study aimed to identify the mechanism of regulation. In a mouse model of MI, neutrophil mobilization to blood and recruitment to the heart were higher in 11β-HSD1-deficient (Hsd11b1-/-) relative to wild-type (WT) mice, despite similar initial injury and circulating glucocorticoid. In bone marrow chimeric mice, neutrophil mobilization was increased when 11β-HSD1 was absent from host cells, but not when absent from donor bone marrow-derived cells. Consistent with a role for 11β-HSD1 in 'host' myocardium, gene expression of a subset of neutrophil chemoattractants, including the chemokines Cxcl2 and Cxcl5, was selectively increased in the myocardium of Hsd11b1-/- mice relative to WT. SM22α-Cre directed disruption of Hsd11b1 in smooth muscle and cardiomyocytes had no effect on neutrophil recruitment. Expression of Cxcl2 and Cxcl5 was elevated in fibroblast fractions isolated from hearts of Hsd11b1-/- mice post MI and provision of either corticosterone or of the 11β-HSD1 substrate, 11-dehydrocorticosterone, to cultured murine cardiac fibroblasts suppressed IL-1α-induced expression of Cxcl2 and Cxcl5. These data identify suppression of CXCL2 and CXCL5 chemoattractant expression by 11β-HSD1 as a novel mechanism with potential for regulation of neutrophil recruitment to the injured myocardium, and cardiac fibroblasts as a key site for intracellular glucocorticoid regeneration during acute inflammation following myocardial injury.


Publication metadata

Author(s): Mylonas KJ, Turner NA, Bageghni SA, Kenyon CJ, White CI, McGregor K, Kimmitt RA, Sulston R, Kelly V, Walker BR, Porter KE, Chapman KE, Gray GA

Publication type: Article

Publication status: Published

Journal: Journal of Endocrinology

Year: 2017

Volume: 233

Issue: 3

Pages: 315-327

Print publication date: 01/06/2017

Acceptance date: 11/04/2017

Date deposited: 22/12/2017

ISSN (print): 0022-0795

ISSN (electronic): 1479-6805

Publisher: BioScientifica Ltd

URL: https://doi.org/10.1530/JOE-16-0501

DOI: 10.1530/JOE-16-0501

PubMed id: 28522730


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Funding

Funder referenceFunder name
FS/09/053
PG/11/110/29248
WT083184
WT091720MA

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