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Glucocorticoid-induced leucine zipper: a critical factor in macrophage endotoxin tolerance
Jessica Hoppstädter1, Sonja M Kessler1, Stefano Bruscoli2
1Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66041 Saarbrücken, Germany;
Abstract:
Induction of glucocorticoid-induced leucine zipper (GILZ) by glucocorticoids plays a key role in their anti-inflammatory action. In activated macrophages, GILZ levels are downregulated via tristetraprolin-mediated GILZ mRNA destabilization. To assess the functional significance of GILZ downregulation, we generated myeloid-specific GILZ knockout (KO) mice. GILZ-deficient macrophages displayed a higher responsiveness toward LPS, as indicated by increased TNF-α and IL-1β expression. This effect was due to an activation of ERK, which was significantly amplified in GILZ KO cells. The LPS-induced activation of macrophages is attenuated upon pretreatment of macrophages with low-dose LPS, an effect termed endotoxin tolerance. In LPS-tolerant macrophages, GILZ mRNA was stabilized, whereas ERK activation was strongly decreased. In contrast, GILZ KO macrophages exhibited a strongly reduced desensitization. To explore the contribution of GILZ expression in macrophages to endotoxin tolerance in vivo, we treated GILZ KO mice with repeated i.p. injections of low-dose LPS followed by treatment with high-dose LPS. LPS pretreatment resulted in reduced proinflammatory mediator expression upon high-dose LPS treatment in serum and tissues. In contrast, cytokine induction was preserved in tolerized GILZ KO animals. In summary, our data suggest that GILZ is a key regulator of macrophage functions.
Insights
Glucocorticoid-induced leucine zipper (GILZ) is crucial for anti-inflammatory responses. Loss of GILZ in macrophages amplifies inflammatory signaling and impairs endotoxin tolerance, highlighting GILZ
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Glucocorticoids exert anti-inflammatory effects partly through inducing GILZ.
- GILZ expression in macrophages is downregulated by tristetraprolin, affecting inflammatory responses.
- Understanding GILZ's role in macrophage function is critical for inflammatory disease research.
Purpose of the Study:
- To investigate the functional significance of GILZ downregulation in macrophages.
- To elucidate the role of GILZ in regulating macrophage responsiveness to lipopolysaccharide (LPS).
- To determine GILZ's contribution to endotoxin tolerance in vivo and in vitro.
Main Methods:
- Generation of myeloid-specific GILZ knockout (KO) mice.
- Assessment of macrophage responsiveness to LPS, including cytokine expression (TNF-α, IL-1β) and ERK activation.
- Evaluation of endotoxin tolerance in GILZ KO macrophages and mice following LPS pretreatment.
Main Results:
- GILZ-deficient macrophages exhibited heightened responsiveness to LPS, with increased TNF-α and IL-1β production.
- ERK activation was significantly amplified in GILZ-deficient macrophages upon LPS stimulation.
- GILZ KO macrophages showed impaired desensitization to LPS, indicating a defect in endotoxin tolerance.
- In vivo studies confirmed that GILZ deficiency abrogated LPS-induced endotoxin tolerance in mice.
Conclusions:
- GILZ is a key regulator of macrophage inflammatory responses.
- GILZ plays a critical role in the development of endotoxin tolerance.
- Targeting GILZ may offer therapeutic strategies for inflammatory conditions.
