Glucocorticoid-Induced Leucine Zipper: A Promising Marker for Monitoring and Treating Sepsis

Abstract

Sepsis is a clinical syndrome that resulting from a dysregulated inflammatory response to infection that leads to organ dysfunction. The dysregulated inflammatory response transitions from a hyper-inflammatory phase to a hypo-inflammatory or immunosuppressive phase. Currently, no phase-specific molecular-based therapies are available for monitoring the complex immune response and treating sepsis due to individual variations in the timing and overlap of the dysregulated immune response in most patients. Glucocorticoid-induced leucine zipper (GILZ), is broadly present in multiple tissues and circumvent glucocorticoid resistance (GCR) or unwanted side effects. Recently, the characteristics of GILZ downregulation during acute hyperinflammation and GILZ upregulation during the immunosuppressive phase in various inflammatory diseases have been well documented, and the protective effects of GILZ have gained attention in the field of sepsis. However, whether GILZ could be a promising candidate biomarker for monitoring and treating septic patients remains unknown. Here, we discuss the effect of GILZ in sepsis and sepsis-induced immunosuppression.

Keywords: anti-inflammatory; glucocorticoid-induced leucine zipper; glucocorticoids; sepsis; sepsis-induced immunosuppression.

Figure 1

Changes in glucocorticoid production, metabolism, and regulation in sepsis. ① The HPA axis is activated by stress (both physically and mentally), tissue damage, and infection. The paraventricular nucleus of the hypothalamus secretes CRH, and the anterior pituitary gland secretes ACTH or corticotropin; then GC is secreted by the adrenal cortex. Cytokines such as IL-1β, TNF-α, and IL-6 can be projected in the hypothalamus through neuroafferent projections. DAMPs and PAMPs can also directly stimulate adrenocortical cells with toll receptors (TLR), leading to the synthesis of ACTH dependent cortisol. Circulating inflammatory mediators break the brain barrier and act on the hypothalamus. GC exerts negative feedback on both CRH and ACTH production when GC exceeds the threshold. ② Then 5% GC that is free and activated binds the GR and enters the nucleus to influence gene expression. The inactive GC could be reactivated by 11b-HSD1. GR binds promoters to promote metabolic genes and anti-inflammation genes. Additionally, GR binds negative GRE elements (nGRE) on DNA or some transcription factors (TF) to inhibit the expression of target genes. ③75% GC bound to CBG is transported to various tissue. During sepsis, the host protein production is reduced and the CBG in the inflammatory site is cleaved by neutrophil elastases. Cortisol is cleared mainly through A-ring reductases in the liver and through 11β-HSD2 in the kidneys. These enzymes are limited in sepsis resulting in reduced clearance of GC. PAMPs: pathogen-associated molecular patterns; DAMPs: damage-associated molecular patterns; HPA: hypothalamic–pituitary–adrenal axis; CRH: corticotropin-releasing hormone; ACTH: adrenocorticotropic hormone; CBG: corticosteroid-binding globulin; 11β-HSD2: 11b-hydroxysteroid dehydrogenase type 2; 11b-HSD1: 11b-hydroxysteroid dehydrogenase type 1.

Figure 2

Major signaling pathways of GILZ. GILZ can regulate cell activation, apoptosis, proliferation, and inflammation mainly through several signaling pathways. GILZ directly binds p65 and p52 to inhibit NF-κB signaling to reduce the production of proinflammatory factors and macrophage phagocytosis. GILZ can directly bind Ras and inhibit downstream pathways. (1) inhibits the PI3K–Akt pathway to regulate apoptosis and cell survival; GILZ inhibits FOXO3A-mediated transcription, such as the pro-apoptotic protein, Bim. (2) The direct binding of GILZ to Ras and Raf leads to reduced activation of MEK, ERK, and MAPK, which inhibits cell growth and proliferation. (3) GILZ can directly bind c-Fos and c-Jun to inhibit AP-1 signaling, which prevents cell growth, cell differentiation, and inflammation. NF-κB, nuclear factor κB; AP-1, activator protein 1; FoxO3, forkhead box protein O3; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; AKT: Protein kinase B (PKB), also known as Akt.