Pro-inflammatory glucocorticoid effects in the CNS

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DESCRIPTION (provided by applicant): Glucocorticoids (GCs), the adrenal steroids secreted during stress, can compromise the ability of neurons to survive necrotic neurological insults. These deleterious effects have often been viewed as counterbalanced by the benefits of the anti-inflammatory actions of GCs in the injured brain. However, GCs are actually less consistently anti-inflammatory in the injured brain than generally assumed. Moreover, as a marked challenge to dogma, recent work from my lab and others has shown that GCs can even potentiate aspects of inflammation in the injured hippocampus and cortex (while being classically anti-inflammatory elsewhere in the brain). Specifically, the hormone augments the migration of inflammatory cells to the injury site, the expression of and protein levels of pro-inflammatory cytokines, and the activation of the pro- inflammatory transcription factor NFkB. These findings are challenging at the basic science level (i.e., uncovering how GCs can have opposite effects on inflammation in different contexts); moreover, they are of considerable potential clinical relevance, given the enormous use of synthetic GCs to control post-insult inflammation in the human brain. This proposal will study the mechanisms underlying these novel GC actions at a more reductive level than in previous studies. In all experiments, intact rats will be exposed to either LPS, a bacteria-derived molecule which stimulates a robust inflammatory response, or a seizure-inducing excitotoxin, which also causes inflammation in the brain. Specific Aim 1 will analyze how the magnitude and duration of GC exposure, its temporal relationship to one of these inflammatory challenges, and the brain region examined determine whether GCs worsen or blunt the inflammation caused by these challenges. From these data, we will identify the most striking contrasts between conditions where GCs augment versus blunt facets of inflammation. In Specific Aim 2, we will identify gene expression profiles that differentiate between those two states; specifically, we will identify genes whose expression is influenced in a contrasting manner by GCs, depending on whether the hormone is enhancing or inhibiting. Specific Aim 3 will then identify the cell types in which these expression differences are occurring (i.e., whether in neurons, astrocytes, microglia, endothelial cells, neutrophils or macrophages). PUBLIC HEALTH RELEVANCE: Glucocorticoids (GCs, including synthetic corticosteroids such as hydrocortisone or prednisone) are anti-inflammatory, and are widely used to decrease the damaging inflammation that occurs after brain injury. However, a growing literature shows that GCs can actually worsen inflammation following some acute neurological insults. The proposal begins to dissect the molecular mechanisms underlying these unexpected and damaging pro-inflammatory GC effects.