New insights into the cell- and tissue-specificity of glucocorticoid actions

Abstract

Glucocorticoids (GCs) are endogenous hormones that are crucial for the homeostasis of the organism and adaptation to the external environment. Because of their anti-inflammatory effects, synthetic GCs are also extensively used in clinical practice. However, almost all cells in the body are sensitive to GC regulation. As a result, these mediators have pleiotropic effects, which may be undesirable or detrimental to human health. Here, we summarize the recent findings that contribute to deciphering the molecular mechanisms downstream of glucocorticoid receptor activation. We also discuss the complex role of GCs in infectious diseases such as sepsis and COVID-19, in which the balance between pathogen elimination and protection against excessive inflammation and immunopathology needs to be tightly regulated. An understanding of the cell type- and context-specific actions of GCs from the molecular to the organismal level would help to optimize their therapeutic use.

Keywords: Glucocorticoids; immune response; inflammation.

Fig. 1

Genomic signaling mediated by GR. Upon binding to GCs, GR is translocated to the nucleus, where it regulates gene expression by directly binding to DNA or other transcription factors (TFs). (1) The GR homodimer binds to a GC responsive element (GRE) or inverted repeated negative GRE (nGRE), leading to gene transcription or repression, respectively. (2) The GR monomer binds to half the GRE (hGRE) close to the binding site of another TF (TFBS), resulting in gene transcription or repression. Without directly binding to DNA, the GR monomer can physically interact with another TF, thereby influencing its activity (3) or preventing its binding to DNA. (4) GR can also compete with other TFs for binding to DNA (5) or co-factors (CFs) required for transcription (6)

Fig. 2

Factors regulating the transcriptional response to GCs in the cell. The transcriptional program activated in response to GCs results from the complex integration of signals from within and outside the cell. This program depends, first and foremost, on the target cell type and basal expression of target genes. (1) The chromatin accessibility of the promoter regulates transcriptional machinery recruitment. (2) GR activity is also regulated by interactions with other transcription factors (TFs). (3) Finally, the presence of other cells and extracellular molecules determines the microenvironment, (4) which significantly affects the response to GCs

Fig. 3

New targets for GCs in immune and nonimmune cells. Recently identified target molecules of GR are shown. The cell- and context-specificity of GC regulation is mediated by the pathological condition and the cell type in which the GC targets are located. The consequences of such regulation, which are dependent on context, and the reference numbers are also reported