Microglial cells of the central nervous system are responsible for initiating the inflammatory response that activates the immune system and tissue repair processes following microbial infection or tissue damage. However, dysregulation of microglia-induced inflammation can lead to neuronal dysfunction and cell death. Because microglia are involved in the onset of experimental autoimmune encephalomyelitis (EAE; a model of multiple sclerosis) and oestrogen modifies the progression of EAE, the authors first tested whether two synthetic ERβ-specific ligands (which were based on a halogen-substituted phenyl-2H-indazole core and were referred to as indazole-Br and indazole-Cl) could suppress the transcriptional activation of pro-inflammatory genes and increase cytokine secretion in cultured microglia. In contrast to 17β-oestradiol, the endogenous ligand for ERβ, indazole-Br and indazole-Cl suppressed the production of pro-inflammatory mediators in response to a challenge with lipopolysaccharide. Inflammatory mediators that were repressed included those that are required for the differentiation and activation of T helper 17 cells (TH17 cells), a subset of T helper cells that is involved in the pathogenesis of multiple sclerosis.
The observation that 17β-oestradiol was less effective at inhibiting inflammatory responses than indazole-Br or indazole-Cl suggested to the authors that endogenous steroids other than 17β-oestradiol might be involved in the regulation of microglia-induced inflammation. They therefore screened a panel of steroids and identified 5-androstene-3β,17β-diol (ADIOL) as an endogenous steroid that binds to ERβ and produces effects similar to those of indazole-Cl and indazole-Br.
This is a preview of subscription content, access via your institution