Glucocorticoids: Protectors of the brain during innate immune responses

The innate immune response is a coordinated set of reactions involving cells of myeloid lineage and a network of signaling molecules. Such a response takes place in the CNS during trauma, stroke, spinal cord injury, and neurodegenerative diseases, suggesting that macrophages/microglia are the cells that perpetuate the progressive neuronal damage. However, there is accumulating evidence that these cells and their secreted proinflarnmatory molecules have more beneficial effects than detrimental consequences for the neuronal elements. Indeed, a timely controlled innate immune response may limit toxicity in swiftly eliminating foreign materials and debris that are known to interfere with recovery and regeneration. Each step of the immune cascade is under the tight control of stimulatory and inhibitory signals. Glucocorticoids (GCs) act as the critical negative feedback on all myeloid cells, including those present within the brain parenchyma. Because too little is like too much, both an inappropriate feedback of GCs on microglia and high circulating GC levels in stressed individuals have been associated with deleterious consequences for the brain. In this review, the authors discuss both sides of the story with a particular emphasis on the neuroprotective role of endogenous GCs during immune challenges and the problems in determining whether GCs can be a good therapy for the treatment of neuropathological conditions.