Abstract
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.
Highlights
While the adaptive immune system usually deteriorates with age, innate immune cells can cause a chronic, low-grade systemic inflammatory state, termed “inflammaging” (Franceschi et al, 2000)
The prevalence and mortality associated with CVD are expected to grow exponentially, as the world population continues to age (Costantino, Paneni, & Cosentino, 2016)
Rather than solely detrimental, such changes represent an adaptive/remodeling response that results in dysregulated homeostasis of immunity, and of other systems that influence and are influenced by the immune system, such as the nervous and endocrine systems (Fulop et al, 2017)
Summary
While the adaptive immune system usually deteriorates with age, innate immune cells can cause a chronic, low-grade systemic inflammatory state, termed “inflammaging” (Franceschi et al, 2000). Senescent cells (SCs) are characterized by elevated cytokine production, upregulation of the cyclin-dependent kinase inhibitors p16 (Cdkn2a) and p21 (Cdkn1a), and downregulation of the senescence suppressor sirtuin-1 (Sirt1) (Lee, Lee, Lee, & Min, 2019; Tchkonia, Zhu, van Deursen, Campisi, & Kirkland, 2013; van Deursen, 2014) None of these effects were observed in PMs obtained from aged mice, indicating that these macrophages do not resemble SCs (Figure 1g). The gene expression of Hsd11b2, the isozyme that exerts dehydrogenase (cortisol/corticosterone to cortisone/11-DHC) activity, remained unchanged in PMs and PBLs from aged mice compared with young controls (Figure S2b). The downregulation of the enzyme was paralleled by lower levels of intracellular conversion of cortisone to cortisol (Figure 3d,e) These findings suggested that reduced 11β-HSD1 expression translates into less corticosterone available to activate the GR in aging macrophages in the in vivo setting. TNF production, generation of reactive oxygen species, and ERK phosphorylation were increased both in macrophages from aged WT as well as young KO animals, indicating that the downregulation of GILZ might be a central feature of inflammaging
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