Altered glucocorticoid metabolism represents a feature of macroph‐aging

Perez, Jenny Vanessa Valbuena; Linnenberger, Rebecca; Dembek, Anna; Bruscoli, Stefano; Riccardi, Carlo; Schulz, Marcel H.; Meyer, Markus R.; Kiemer, Alexandra K.; Hoppstädter, Jessica

doi:10.1111/acel.13156

Cited by 32 publications

(21 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This detailed kinetic study of the degree of splenomegaly confirms that GILZ deficiency is permissive of the development of autoimmunity triggered by underlying genetic factors. GILZ has recently been reported to decrease in murine macrophages as a function of the mild inflammatory state that develops with age (33). We previously showed that Lyn -/mice expressed lower GILZ, like patients with SLE, and this deficiency worsened with age (12).…”

Section: Gilz Deficiency Increased Spleen Weight In Lyn-deficient Micementioning

confidence: 78%

GILZ Regulates the Expression of Pro-Inflammatory Cytokines and Protects Against End-Organ Damage in a Model of Lupus

et al. 2021

View full text Add to dashboard Cite

Glucocorticoid-induced leucine zipper (GILZ) mimics many of the anti-inflammatory effects of glucocorticoids, suggesting it as a point of therapeutic intervention that could bypass GC adverse effects. We previously reported that GILZ down-regulation is a feature of human SLE, and loss of GILZ permits the development of autoantibodies and lupus-like autoimmunity in mice. To further query the contribution of GILZ to protection against autoimmune inflammation, we studied the development of the lupus phenotype in Lyn-deficient (Lyn-/-) mice in which GILZ expression was genetically ablated. In Lyn-/- mice, splenomegaly, glomerulonephritis, anti-dsDNA antibody titres and cytokine expression were exacerbated by GILZ deficiency, while other autoantibody titres and glomerular immune complex deposition were unaffected. Likewise, in patients with SLE, GILZ was inversely correlated with IL23A, and in SLE patients not taking glucocorticoids, GILZ was also inversely correlated with BAFF and IL18. This suggests that at the onset of autoimmunity, GILZ protects against tissue injury by modulating pro-inflammatory pathways, downstream of antibodies, to regulate the cycle of inflammation in SLE.

show abstract

Section: Gilz Deficiency Increased Spleen Weight In Lyn-deficient Micementioning

confidence: 78%

GILZ Regulates the Expression of Pro-Inflammatory Cytokines and Protects Against End-Organ Damage in a Model of Lupus

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Quaitative RT-PCR was performed as described previously [ 35 , 36 , 44 ]. RNA was reverse transcribed using the High-Capacity cDNA Reverse Transcription Kit (#4368813, Thermo Fisher Scientific, Waltham, MA, USA), in the presence of RNase inhibitor (RNaseOUT™, #10777019, Thermo Fisher Scientific, Waltham, MA, USA), following the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background Based on reports on elevated cholesterol levels in cancer cells, strategies to lower cholesterol synthesis have been suggested as an antitumour strategy. However, cholesterol depletion has also been shown to induce tumour-promoting actions in tumour-associated macrophages (TAMs). Methods We performed lipidomic and transcriptomic analyses of human lung cancer material. To assess whether the TAM phenotype is shaped by secreted factors produced by tumour cells, primary human monocyte-derived macrophages were polarized towards a TAM-like phenotype using tumour cell-conditioned medium. Findings Lipidomic analysis of lung adenocarcinoma (n=29) and adjacent non-tumour tissues (n=22) revealed a significant accumulation of free cholesterol and cholesteryl esters within the tumour tissue. In contrast, cholesterol levels were reduced in TAMs isolated from lung adenocarcinoma tissues when compared with alveolar macrophages (AMs) obtained from adjacent non-tumour tissues. Bulk-RNA-Seq revealed that genes involved in cholesterol biosynthesis and metabolism were downregulated in TAMs, while cholesterol efflux transporters were upregulated. In vitro polarized TAM-like macrophages showed an attenuated lipogenic gene expression signature and exhibited lower cholesterol levels compared with non-polarized macrophages. A genome-wide comparison by bulk RNA-Seq confirmed a high similarity of ex vivo TAMs and in vitro TAM-like macrophages. Modulation of intracellular cholesterol levels by either starving, cholesterol depletion, or efflux transporter inhibition indicated that cholesterol distinctly shapes macrophage gene expression. Interpretation Our data show an opposite dysregulation of cholesterol homeostasis in tumour tissue vs. TAMs. Polarization of in vitro differentiated macrophages by tumour cell-conditioned medium recapitulates key features of ex vivo TAMs.

show abstract

“…During inflammation, 11β-HSD1 has been reported to be upregulated. 11β-HSD1-deficient mice exhibited delayed acquisition of macrophage phagocytic capacity, whereas cytokine production in macrophages lacking 11β-HSD1 was increased (Zhang et al, 2005;Gilmour et al, 2006;Coutinho et al, 2016;Valbuena Perez et al, 2020). Thus, the systemic inhibition of 11β-HSD1 increase inflammation, which would be detrimental in NAFLD.…”

Section: Discussionmentioning

confidence: 99%

5-Bis-(2,6-difluoro-benzylidene) Cyclopentanone Acts as a Selective 11β-Hydroxysteroid Dehydrogenase one Inhibitor to Treat Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

Guan

Wang

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

Background: 11β-Hydroxysteroid dehydrogenase one is responsible for activating inert glucocorticoid cortisone into biologically active cortisol in humans and may be a novel target for the treatment of nonalcoholic fatty liver disease.Methods: A series of benzylidene cyclopentanone derivatives were synthesized, and the selective inhibitory effects on rat, mouse and human 11β-hydroxysteroid dehydrogenase one and two were screened. The most potent compound [5-bis-(2,6-difluoro-benzylidene)-cyclopentanone] (WZS08), was used to treat nonalcoholic fatty liver disease in mice fed a high-fat-diet for 100 days.Results: WZS08 was the most potent inhibitor of rat, mouse, and human 11β-hydroxysteroid dehydrogenase 1, with half maximum inhibitory concentrations of 378.0, 244.1, and 621.1 nM, respectively, and it did not affect 11β-hydroxysteroid dehydrogenase two at 100 μM. When mice were fed WZS08 (1, 2, and 4 mg/kg) for 100 days, WZS08 significantly lowered the serum insulin levels and insulin index at 4 mg/kg. WZS08 significantly reduced the levels of serum triglycerides, cholesterol, low-density lipoprotein, and hepatic fat ratio at low concentration of 1 mg/kg. It down-regulated Plin2 expression and up-regulated Fabp4 expression at low concentration of 1 mg/kg. It significantly improved the morphology of the non-alcoholic fatty liver.Conclusion: WZS08 selectively inhibits rat, mouse, and human 11β-hydroxysteroid dehydrogenase 1, and can treat non-alcoholic fatty liver disease in a mouse model.

show abstract

Altered glucocorticoid metabolism represents a feature of macroph‐aging

Cited by 32 publications

References 61 publications

GILZ Regulates the Expression of Pro-Inflammatory Cytokines and Protects Against End-Organ Damage in a Model of Lupus

GILZ Regulates the Expression of Pro-Inflammatory Cytokines and Protects Against End-Organ Damage in a Model of Lupus

Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages

5-Bis-(2,6-difluoro-benzylidene) Cyclopentanone Acts as a Selective 11β-Hydroxysteroid Dehydrogenase one Inhibitor to Treat Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

Contact Info

Product

Resources

About