Glucocorticoids promote apoptosis of proinflammatory monocytes by inhibiting ERK activity

Abstract

Glucocorticoids (GCs) are potent anti-inflammatory drugs whose mode of action is complex and still debatable. One likely cellular target of GCs are monocytes/macrophages. The role of GCs in monocyte survival is also debated. Although both granulocyte macrophage-colony stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) are important regulators of macrophage lineage functions including their survival, the former is often associated with proinflammatory functions while the latter is important in lineage homeostasis. We report here that the GC, dexamethasone, induces apoptosis in GM-CSF-treated human monocytes while having no impact on M-CSF-induced monocyte survival. To understand how GCs, GM-CSF, and M-CSF are regulating monocyte survival and other functions during inflammation, we firstly examined the transcriptomic changes elicited by these three agents in human monocytes, either acting alone or in combination. Transcriptomic and Ingenuity pathway analyses found that dexamethasone differentially modulated dendritic cell maturation and TREM1 signaling pathways in GM-CSF-treated and M-CSF-treated monocytes, two pathways known to be regulated by ERK1/2 activity. These analyses led us to provide evidence that the GC inhibits ERK1/2 activity selectively in GM-CSF-treated monocytes to induce apoptosis. It is proposed that this inhibition of ERK1/2 activity leads to inactivation of p90 ribosomal-S6 kinase and Bad dephosphorylation leading in turn to enhanced caspase-3 activity and subsequent apoptosis. Furthermore, pharmacological inhibition of GC receptor activity restored the ERK1/2 signaling and prevented the GC-induced apoptosis in GM-CSF-treated monocytes. Increased tissue macrophage numbers, possibly from enhanced survival due to mediators such as GM-CSF, can correlate with inflammatory disease severity; also reduction in these numbers can correlate with the therapeutic benefit of a number of agents, including GCs. We propose that the ERK1/2 signaling pathway promotes survival of GM-CSF-treated proinflammatory monocytes, which can be selectively targeted by GCs as a novel mechanism to reduce local monocyte/macrophage numbers and hence inflammation.

Dexamethasone induces aberrant macrophage immune function and apoptosis

“…Overexpression of KLF9 induces apoptosis in macrophage cells. GCs were previously demonstrated to activate the intrinsic apoptotic pathways in a tumor model (4). in the present study, it was proposed that KLF9, which was induced by Dex, would activate apoptosis in macrophage cells.…”

“…GCs have been used for the early treatment of rheumatoid arthritis, and have since become the most common therapy for inflammatory disorders (4). GCs remain very effective anti-inflammatory and immunosuppressive agents used in the treatment of numerous autoimmune diseases (1).…”

“…Translocated GR can directly bind to a canonical GC response element or act indirectly by interaction with other transcription factors (2). The generally accepted view of anti-inflammatory actions on macrophages is through the suppression of NF-κB activity, thus inhibiting the transcription of proinflammatory genes (3,4). Accumulating evidence has demonstrated that other than the ability to suppress macrophage production of proinflammatory mediators, GCs can directly induce specific changes in cell survival, proliferation, and phagocytosis to suppress inflammation (5).…”

Microenvironmental signals govern the cellular identity of testicular macrophages

“…The anti‐inflammatory function of GC was further confirmed by increased levels of the anti‐inflammatory cytokine IL‐10, as well as CD163 and other M2 macrophage markers . Moreover, GC promotes the death of proinflammatory monocytes by attenuating the ERK signaling pathways . GC treatment mediates the up‐regulation of CD163 and GR‐1 , but decreases the expression of CX3CR1 .…”

“…105 Moreover, GC promotes the death of proinflammatory monocytes by attenuating the ERK signaling pathways. 106 GC treatment mediates the up-regulation of CD163 and GR-1, but decreases the expression of CX3CR1. 107 Surprisingly, the corticosterone level in testicular IF is very high compared to levels in the serum and aqueous humor of the eye, another immune privileged organ.…”