Researchers have uncovered an unexpected role for estrogen receptors in the brain in keeping inflammation under control. The findings reported in the May 13 issue of the Cell Press journal Cell may have important implications for the treatment of multiple sclerosis (MS) and many other neurodegenerative diseases. They might also help to explain why women are three times more susceptible to developing MS than men are, researchers say.
"We've really discovered an alternative pathway for estrogen receptors in the brain," said Christopher Glass of the University of California, San Diego.
Estrogen receptors are primarily known to activate programs of gene expression, he explained. In this case, however, estrogen receptors are critical for turning off genes that would otherwise lead to chronic inflammation.
The estrogen receptor (ER) in question is not the classical ERα ones responsible for the sex-specific effects of estrogen. Rather, they are related receptors known as ERβ found in cells of the brain known as microglia and astrocytes. Microglia serve as sentinels of infection and injury in the brain. Upon detection of microbial invasion or evidence of tissue damage, microglia rapidly initiate an inflammatory response that serves to recruit the immune system and tissue repair processes. Among other roles, astrocytes also sense infection and injury, and amplify the immune reaction initiated by microglia.
Both ERα and ERβ respond to the hormone estradiol, the major form of estrogen in humans. Glass and study first author Kaoru Saijo now show that ERβ also responds to a second hormone called ADIOL as well. That ADIOL is converted by special enzymes from its precursor DHEA in microglia.
When levels of either ADIOL or ERβ were experimentally reduced, cells and animals showed an exaggerated inflammatory response. On the other hand, treatment with either ADIOL or synthetic molecules designed to specifically target ERβ prevented inflammation and its effects in mice with experimental autoimmune encephalomyelitis, a condition that closely mimics MS in humans.
Although MS is a very complicated disease, the findings suggest drugs targeted at the ERβ receptors might effectively shut down the inflammation that goes along with the disease, Saijo said. The same principle might also work in the treatment of other neurodegenerative conditions associated with inflammation, including Parkinson's, Alzheimer's and HIV-associated dementia.
The findings might also help to explain the strong sex bias in MS, which disproportionately affects relatively young women. "When ERβ receptors see estradiol, they may kick ADIOL out leaving the brain more susceptible to inflammation," Saijo said. In other words, estradiol and ADIOL compete for ERβ and in that competition estradiol will generally win.
"Although the estrogen receptors (ERs) have been implicated in the etiology of MS, no clear molecular mechanisms link them to relapsing-remitting MS," wrote David Gosselin and Serge Rivest in an accompanying commentary. "Now in this issue of Cell, Saijo and colleagues may have filled in this gap."
In addition to explaining why females develop MS more often than males, Gosselin and Rivest continued, the findings also suggest that birth control medications and environmental factors such as estrogen analogs derived from plants might also promote development of the disease.
"The possibility arises from our study that estradiol can antagonize the anti-inflammatory effects of ADIOL," Glass said. "This may lead to a shift in the balance from anti-inflammatory to inflammatory."
Glass and Saijo say they plan to further explore the role of this pathway in other neurodegenerative diseases. They note that inflammation plays some role in most any of those conditions you can name, though it isn't always clear whether it is a cause or consequence.
ADIOL levels in the blood or spinal fluid might also prove to be a useful biomarker for inflammation, they said. The findings also suggest that genetic variants in this pathway, including in the enzyme needed to produce ADIOL, should be considered prime candidates for MS susceptibility genes.