Abstract
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.
Highlights
Ischemic cell death associated with myocardial infarction (MI) prompts the recruitment and activation of immune cells to ensure repair (Epelman & Mann 2012, Frangogiannis2012)
We found that early neutrophil recruitment to the injured myocardium increases in 11β-HSD1-deficient mice following induction of MI by coronary artery ligation, and this is associated with increased pro-reparative macrophage polarization and reduced detrimental remodeling (McSweeney et al 2010)
The present study aimed to investigate whether changes in myocardial neutrophil content are accompanied by changes in neutrophil mobilization from bone marrow to the blood; whether myocardial neutrophil chemoattractant expression post MI is influenced by 11β-HSD1 availability and key cellular sites of 11β-HSD1 expression that determine neutrophil recruitment
Summary
Ischemic cell death associated with myocardial infarction (MI) prompts the recruitment and activation of immune cells to ensure repair We found that early neutrophil recruitment to the injured myocardium increases in 11β-HSD1-deficient mice following induction of MI by coronary artery ligation, and this is associated with increased pro-reparative macrophage polarization and reduced detrimental remodeling (McSweeney et al 2010). This suggests a key role for intracellular corticosteroid regeneration in regulating neutrophil recruitment to the injured heart, but the underlying mechanisms are unknown (Gray et al 2017). The present study aimed to investigate whether changes in myocardial neutrophil content are accompanied by changes in neutrophil mobilization from bone marrow to the blood; whether myocardial neutrophil chemoattractant expression post MI is influenced by 11β-HSD1 availability and key cellular sites of 11β-HSD1 expression that determine neutrophil recruitment
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