Transrepression of Inflammation

Science Signaling  17 May 2011:
Vol. 4, Issue 173, pp. ec141
DOI: 10.1126/scisignal.4173ec141

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is characterized by inflammation and demyelination of neurons (see commentary by Gosselin and Rivest). MS is mediated by microglia, which are macrophage-like cells resident in the CNS, and T helper 1 (TH1) and TH17 cells, which are proinflammatory T cell subsets that infiltrate the CNS. Estrogens and synthetic ligands of estrogen receptors (ERs) have beneficial outcomes in mice with experimental autoimmune encephalitis (EAE), a mouse model of MS, through their anti-inflammatory effects, but the mechanisms involved are unclear. Saijo et al. showed that ERβ was more abundant than ERα in mouse microglia and that synthetic ERβ-specific ligands (such as Indazole-Cl), but not ERα-specific ligands (such as 17β-estradiol), blocked the expression of proinflammatory genes in microglia and astrocytes in vitro. Indazole-Cl prevented the development of EAE in mice when administered before the onset of paralysis, as well as promoting resolution of EAE when provided to mice after they exhibited symptoms of disease. The authors identified ADIOL as an endogenous ERβ ligand that prevented the expression of proinflammatory genes in microglia and inhibited the development of EAE in mice. Expression of the proinflammatory genes examined in this study requires the transcription factor AP-1. Saijo et al. showed that ADIOL-stimulated ERβ blocked the function of AP-1 in microglia by binding to AP-1 at promoter sites and recruiting the corepressor protein CtBP, a mechanism known as transrepression. Together, these data suggest an ERβ-specific, anti-inflammatory mechanism in microglia that may provide an effective therapeutic target for the treatment of MS.

K. Saijo, J. G. Collier, A. C. Li, J. A. Katzenellenbogen, C. K. Glass, An ADIOL-ERβ-CtBP transrepression pathway negatively regulates microglia-mediated inflammation. Cell 145, 584–595 (2011). [Online Journal]

D. Gosselin, S. Rivest, Estrogen receptor transrepresses brain inflammation. Cell 145, 495–497 (2011). [Online Journal]