Cell-Specific Immune Regulation by Glucocorticoids in Murine Models of Infection and Inflammation

Abstract

Glucocorticoids (GC) are highly potent negative regulators of immune and inflammatory responses. Effects of GC are primarily mediated by the glucocorticoid receptor (GR) which is expressed by all cell types of the immune system. It is, therefore, difficult to elucidate how endogenous GC mediate their effects on immune responses that involve multiple cellular interactions between various immune cell subsets. This review focuses on endogenous GC targeting specific cells of the immune system in various animal models of infection and inflammation. Without the timed release of these hormones, animals infected with various microbes or challenged in inflammatory disease models succumb as a consequence of overshooting immune and inflammatory responses. A clearer picture is emerging that endogenous GC thereby act in a cell-specific and disease model-dependent manner, justifying the need to develop techniques that target GC to individual immune cell types for improved clinical application.

Keywords: B cell; T cell; glucocorticoid; glucocorticoid receptor; innate lymphoid cell; macrophage; myeloid cell; regulatory T cell.

Figure 1

Immune cell-specific targeting by both endogenous and exogenous GC. Various immune cell types were experimentally targeted for GR deletion and then tested in animal models of infection and inflammation for actions by either endogenously released GC (left panel) or exogenous treatment with GC (right panel), or both. Disease models that are affected by impaired GR signaling in a certain immune cell type are indicated as green boxes in the central ovals. Animal models of disease not affected by impaired GR signaling in particular cells are depicted as boxes bordered by dashed lines. Cell type-specific regulation of inflammation and immunity by GC is seen, for example, in Ag-induced arthritis where T cells, but not B cells or myeloid cells, are targeted by GC (right panel). The red arrow means: ‘increased’ or ‘enhanced’. Created with BioRender.com (accessed on 24 April 2022).

Figure 2

Cytokine hyperproduction, but not microbial load determines death or survival when GR signaling is impaired. Viruses, bacteria and parasites all induce effective immune responses by the host that are able to control these microbes. However, proinflammatory cytokine production must, in turn, be kept in check by endogenous GC-induced GR signaling (left path) because a lack of these hormones, or blocking GR signaling, may lead to cytokine hyperproduction, systemic inflammation and death (right path). So far, the cell type(s) targeted by GC have been identified in two experimental animal models: (i) a MCMV infection model where GC feedback on NK and ILC-1 cells [12]; and (ii) a Toxoplasma gondii infection model where GC feedback on T cells [19]. See Section 2.6 for details. Created with BioRender.com (accessed on 24 April 2022).