Glucocorticoids as Regulators of Macrophage-Mediated Tissue Homeostasis

Abstract

Our immune system has evolved as a complex network of cells and tissues tasked with maintaining host homeostasis. This is evident during the inflammatory responses elicited during a microbial infection or traumatic tissue damage. These responses seek to eliminate foreign material or restore tissue integrity. Even during periods without explicit disturbances, the immune system plays prominent roles in tissue homeostasis. Perhaps one of the most studied cells in this regard is the macrophage. Tissue-resident macrophages are a heterogenous group of sensory cells that respond to a variety of environmental cues and are essential for organ function. Endogenously produced glucocorticoid hormones connect external environmental stress signals with the function of many cell types, producing profound changes in immune cells, including macrophages. Here, we review the current literature which demonstrates specific effects of glucocorticoids in several organ systems. We propose that tissue-resident macrophages, through glucocorticoid signaling, may play an underappreciated role as regulators of organ homeostasis.

Keywords: glucocorticoid receptor; glucocorticoids; homeostasis; inflammation; macrophages.

Figure 1

Schematic representation of how glucocorticoids could contribute to cardiac tissue homeostasis. Upon damage or stress activation, glucocorticoid-activated cardiac macrophages promote the active elimination of hypertrophic cardiomyocyte-derived mitochondria and help maintain cardiac health and homeostasis through the induction of the phagocytic receptor Mer tyrosine kinase (Mertk).

Figure 2

Schematic representation of how glucocorticoids could contribute to central nervous system homeostasis. During hippocampal neurogenesis, cell debris derived from apoptotic newborn cells and stress-induced glucocorticoid secretion promote microglia activation and transcriptional induction of the phagocytic receptor Mertk to regulate the production of new neurons in order to maintain homeostasis in the adult hippocampal neurogenic niche.

Figure 3

Proposed model of how the lack of glucocorticoid receptor (GR) in macrophages could be detrimental to gastrointestinal tissue homeostasis. In the dextran sodium sulfate (DSS)-induced colitis model, deletion of GR in myeloid cells delays the resolution of inflammation through an increase in the number of pro-inflammatory macrophages which perpetuates tissue damage. Other immune cells, such as B cells, dendritic cells and ILCs relevant to the intestinal physiology have been deliberately neglected to highlight the function of macrophages.

Figure 4

Schematic representation of how glucocorticoids could contribute to liver homeostasis. Stress and hepatocyte injury around the hepatic sinusoid cause an increase in glucocorticoid levels which induces Kupffer cell activation and IL-10 production. Kupffer cell-derived IL-10 exerts hepatoprotective and tolerogenic effects through Treg activation.