GILZ in sepsis: “Poor is the pupil who does not surpass his master”

Abstract

With the legendary saying of Leonardo da Vinci in the title, we suggest that Glucocorticoid Induced Leucine Zipper (GILZ) may have more promising effects against polymicrobial sepsis, than glucocorticoids (GC). Indeed, the use of GCs in sepsis remains a matter of debate. The rationale for their use in sepsis is to modulate the exaggerated inflammatory response while maintaining innate immunity. However, GC resistance and side‐effects limit their therapeutic value in sepsis. Hence, there is a growing interest in understanding the mechanisms by which GCs modulate immune responses upon infection. In this issue of the European Journal of Immunology, Ellouze et al. provide data demonstrating that deregulated expression of GILZ, a GC‐induced protein, in monocytes/macrophages (M/M) recovered from septic shock patients may contribute to the pathogenesis. Furthermore, the authors demonstrate that GILZ overexpression in M/M improves outcome in septic animals by limiting systemic inflammation while increasing bacterial clearance. Overall, these data provide evidence that GCs may modulate immune responses via GILZ and that GILZ is a valuable alternative for GC therapy in sepsis.

Glucocorticoids in Sepsis: To Be or Not to Be

“…This combination therapy will be further discussed below. Alternatively, administration of GC-induced proteins, such as GILZ, allows working downstream of the GR and thus provides a potential mechanism to circumvent GCR in sepsis (54,55,103). Injection of a TAT-GILZ fusion construct into mice has been shown to protect against LPS-induced endotoxemia (31).…”

Role of GILZ in the Kidney and the Cardiovascular System: Relevance to Cardiorenal Complications of COVID-19

“…Based on their collective findings, authors propose an essential role for GILZ, and monocytes/macrophages, in pathogenesis of septic shock. Indeed, given the limitations of glucocorticoids (e.g., adverse effects and resistance), it is suggested that that GILZ-based options (e.g., cell-permeable GILZ, synthetic GILZ-derived peptide, CRISPRbased transcriptional activators) may represent viable treatment modalities for treatment of sepsis (Vandewalle and Libert, 2020). Studies exploring regulation of macrophage function indicate that GILZ downregulation, via MyD88-dependent and -independent mechanisms, is a consequence of decreased mRNA, reduced translation and/or protein stability, effects promoting macrophage activation (Hoppstädter et al, 2019).…”

“…Importantly, the advent of GILZ-based options (e.g., cell-permeable GILZ fusion protein, synthetic GILZ peptide, GILZ-overexpressing mesenchymal stem cells) has raised the prospect of therapeutic GILZ delivery for a variety of conditions with underlying dysregulation of immune and inflammatory mechanisms hoping to avoid deleterious effects associated with the use of glucocorticoids (Flynn et al, 2019;Vandewalle and Libert, 2020). The demonstrated effects of GILZ on immune and inflammatory responses take added clinical relevance and importance given emerging reports that glucocorticoids (e.g., DEXA) can be of benefit for those This article has not been copyedited and formatted.…”

“…However, glucocorticoids-based therapy causes a number of serious adverse outcomes including elevation in plasma glucose and exacerbation of diabetes mellitus, increased blood pressure and worsening of cardiovascular pathologies (e.g., heart failure), osteoporosis and steroid-induced psychosis, among others; these adverse effects can lead to patient non-compliance and discontinuation of therapy (O'Byrne and Mejza, 2018). The limitations of glucocorticoids therapy has led to a flurry of research to decipher molecular basis of their immune and inflammatory effects with the ultimate objective of harnessing their therapeutic efficacy (e.g., for sepsis) while avoiding their adverse effects (Vandewalle and Libert, 2020). This research has identified GILZ as a pivotal regulator of the impact of glucocorticoids on immune and inflammatory mechanisms, aspects which will be briefly described prior to description of the role of GILZ in the kidney and the cardiovascular system.…”

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

“…Suppression of NF-kB signaling pathways Short-Chain Alcohols Protect Mice from LPS-induced Septic Shock couples GILZ to membrane-penetrating sequences, is an attractive prospect, although further studies are needed to demonstrate the feasibility and safety of GILZ in clinical setting. Alternatively, the targeted activation of GILZ expression using the CRISPR/dCas9 activator complex specifically in macrophages could be used (96). It should be noted that a peptide targeting the C-terminal region of GILZ 115-137 aa in the mouse GILZ sequence has demonstrated a potential therapeutic effect in experimental autoimmune encephalitis (EAE) (97), which suggesting that diverse regions of GILZ can bind different partner proteins.…”