Investigations on the role of GILZ in statin therapy and the influence of glucocorticoid metabolism in age-related inflammation

The glucocorticoid-induced leucine zipper (GILZ) is an immunomodulatory, ubiquitously expressed protein, with multiple roles in different pathophysiological processes. Aim of the present study was to evaluate the role of GILZ and glucocorticoid (GC) metabolism in two different settings: Statins, the most prescribed class of drugs for prevention of cardiovascular disease, exert beneficial lipid-lowering independent effects, as well as muscle-related adverse effects, by mechanisms not fully understood. The role of GILZ in these mechanisms was investigated. Statins were able to induce GILZ expression in skeletal muscle, endothelial cells, and macrophages. Moreover, using in vitro, ex vivo and in vivo approaches, we demonstrated that GILZ is an important mediator of statin-induced muscle damage. The second part of this study focused on aging, which is characterised by a chronic, low-grade inflammatory state —termed “inflammaging”— that contributes to age-related pathogenesis. The elucidation of the mechanisms that modulate this state is of interest to geroscience. Evaluation of the age-associated changes in the myeloid compartment of mice, focusing on glucocorticoid metabolism, showed reduced levels of circulating GCs that, together with perturbations in GC pre-receptor metabolism in aged macrophages, result in dysregulation of the anti-inflammatory networks in these innate immune cells and, thus, might promote the inflammaging phenotype.Der Glukokortikoid-induzierte Leucin Zipper (GILZ) stellt ein ubiquitär exprimiertes Protein dar und spielt eine Rolle in verschiedenen pathophysiologischen Prozessen. Ziel der vorliegenden Studie war es, die Beteiligung von GILZ und des Glukokortikoid (GC)-Metabolismus in zwei Ansätzen zu untersuchen. In der Prävention kardiovaskulärer Erkrankungen stellen Statine die meistverordnete Substanzklasse dar. Neben ihrer Lipid-senkenden Wirkung zeichnen sie pleiotrope Effekte sowie muskelschädigende Nebenwirkungen aus. Zunächst wurde die Hypothese überprüft, dass GILZ für die Vermittlung dieser Prozesse eine Rolle spielt, die nicht in direktem Zusammenhang mit der Lipid-Senkung stehen. Statine führten zu einer Erhöhung der GILZ-Expression in Muskelzellen, Endothelzellen und Makrophagen. Darüber hinaus konnte gezeigt werden, dass GILZ als wichtiger Mediator in der Statin-induzierten Muskelschädigung agiert. Der zweite Teil der Studie fokussierte auf Alterungsprozesse, die sich durch eine chronische, Entzündung auszeichnen. Die Untersuchung alterungsbedingter Änderungen im myeloiden Kompartiment von Mäusen zeigte im Hinblick auf deren GC Metabolismus reduzierte Spiegel zirkulierender GCs. Zusammen mit Störungen im GC Prä-Rezeptor Metabolismus, wie er in alten Mäusen zu finden ist, führt dies zu einer Dysregulation des anti-inflammatorischen Netzwerks dieser Immunzellen, welches zum entzündlichen Phänotyp des Alterns beitragen könnte

Altered glucocorticoid metabolism represents a feature of macroph-aging

The aging process is characterized by a chronic, low-grade inflammatory state, termed "inflammaging." It has been suggested that macrophage activation plays a key role in the induction and maintenance of this state. In the present study, we aimed to elucidate the mechanisms responsible for aging-associated changes in the myeloid compartment of mice. The aging phenotype, characterized by elevated cytokine production, was associated with a dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and diminished serum corticosteroid levels. In particular, the concentration of corticosterone, the major active glucocorticoid in rodents, was decreased. This could be explained by an impaired expression and activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme that determines the extent of cellular glucocorticoid responses by reducing the corticosteroids cortisone/11-dehydrocorticosterone to their active forms cortisol/corticosterone, in aged macrophages and peripheral leukocytes. These changes were accompanied by a downregulation of the glucocorticoid receptor target gene glucocorticoid-induced leucine zipper (GILZ) in vitro and in vivo. Since GILZ plays a central role in macrophage activation, we hypothesized that the loss of GILZ contributed to the process of macroph-aging. The phenotype of macrophages from aged mice was indeed mimicked in young GILZ knockout mice. In summary, the current study provides insight into the role of glucocorticoid metabolism and GILZ regulation during aging

the glucocorticoid induced leucine zipper mediates statin induced muscle damage

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Altered glucocorticoid metabolism represents a feature of macroph-aging

The aging process is characterized by a chronic, low‐grade inflammatory state, termed “inflammaging.” It has been suggested that macrophage activation plays a key role in the induction and maintenance of this state. In the present study, we aimed to elucidate the mechanisms responsible for aging‐associated changes in the myeloid compartment of mice. The aging phenotype, characterized by elevated cytokine production, was associated with a dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis and diminished serum corticosteroid levels. In particular, the concentration of corticosterone, the major active glucocorticoid in rodents, was decreased. This could be explained by an impaired expression and activity of 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1), an enzyme that determines the extent of cellular glucocorticoid responses by reducing the corticosteroids cortisone/11‐dehydrocorticosterone to their active forms cortisol/corticosterone, in aged macrophages and peripheral leukocytes. These changes were accompanied by a downregulation of the glucocorticoid receptor target gene glucocorticoid‐induced leucine zipper (GILZ) in vitro and in vivo. Since GILZ plays a central role in macrophage activation, we hypothesized that the loss of GILZ contributed to the process of macroph‐aging. The phenotype of macrophages from aged mice was indeed mimicked in young GILZ knockout mice. In summary, the current study provides insight into the role of glucocorticoid metabolism and GILZ regulation during aging