Glucocorticoid-Induced Leucine Zipper-Mediated TLR2 Downregulation Accounts for Reduced Neutrophil Activity Following Acute DEX Treatment

Abstract

Glucocorticoids are the most powerful anti-inflammatory and immunosuppressive pharmacological drugs available, despite their adverse effects. Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid-induced gene that shares several anti-inflammatory properties with glucocorticoids. Although immunosuppressive effects of glucocorticoids on neutrophils remain poorly understood, we previously demonstrated that GILZ suppresses neutrophil activation under glucocorticoid treatment. Here, we sought to explore the regulation of Toll-like receptor 2 (TLR2) by the synthetic glucocorticoid dexamethasone (DEX) on neutrophils and the associated GILZ involvement. Peripheral blood neutrophils were isolated from wild type and GILZ-knock-out (KO) mice. TLR2 was found to be downregulated by the in vivo administration of glucocorticoids in wild type but not in GILZ-KO neutrophils, suggesting the involvement of GILZ in TLR2 downregulation. Accordingly, the TLR2-associated anti-fungal activity of neutrophils was reduced by DEX treatment in wild type but not GILZ-KO neutrophils. Furthermore, GILZ did not interact with NF-κB but was found to bind with STAT5, a pivotal factor in the regulation of TLR2 expression. A similar modulation of TLR2 expression, impaired phagocytosis, and killing activity was observed in circulating human neutrophils treated in vitro with DEX. These results demonstrate that glucocorticoids reduce the ability of neutrophils to respond to infections by downregulating TLR2 via GILZ, thereby reducing critical functions.

Antenatal N-acetylcysteine antioxidant therapy relieves lung oxidative stress and related perinatal lethality in HRas/NRas double-null mutant mice

“…Based on our previous detection of increased neutrophil in ltration in the lungs of DKO pups 19 , we sought to analyze whether DEX or NAC antenatal treatment had some effect on lung neutrophil extravasation in these animals. As expected, dexamethasone, a glucocorticoid able to inhibit the immune response 33,34 , produced a complete reversion of neutrophil in ltration in the DKO lungs (Fig. DEX and NAC treatments restore the normal bronchiolar cell architecture in the neonatal DKO lungs Given our previous observations showing a signi cant morphological alteration ( attening) of Club cells (HRas and NRas single and double-KO) and Ciliated cells (only in DKO lungs) 19 , we wished to compare here the structure of these bronchiolar cell lineages in P0 mice before and after receiving antenatal DEX or NAC treatments (Fig.…”

Reduction of fungal dysbiosis is involved in the attenuation of Dextran Sodium Sulfate-Induced Mouse Colitis Mediated by GILZ protein and yeast extract compound

“…Additionally, long-term treatments with some efficacious drugs, such as glucocorticoids and other immunosuppressants, lead to serious adverse effects, including metabolic alterations and increased risk of infections and malignancies (55,56). GILZ is a protein that mediates several anti-inflammatory effects of glucocorticoids, and previous studies on GILZp have reported promising results for the treatment of IBD (6,8,(57)(58)(59)(60). Considering that GILZ is also involved in the pathophysiology of IBD, as demonstrated in both preclinical models of colitis and in patients, in this study, we investigated the effects of combining GILZp with a potential prebiotic yeast extract (Py) in a mouse model of colitis.…”

Exploring the complex interplay: gut microbiome, stress, and leptospirosis

“…The influence of glucocorticoids (GCs) on the regulation of TLR2 expression remains a subject of discussion. Findings from various studies have reported conflicting outcomes, with some indicating downregulation and others suggesting upregulation of TLR2 ( Hoppstädter et al, 2019 ; Ricci et al, 2021 ). Moreover, genetic variations in TLRs have been associated with variations in the severity of leptospirosis.…”