UCLA

Estrogen has well documented neuroprotective effects in a variety of clinical and experimental disorders of the central nervous system (CNS). The beneficial effects of estrogens in CNS disorders include mitigation of clinical symptoms as well as attenuation of histopathological signs of neurodegeneration and inflammation. The cellular mechanisms that underlie these CNS effects of estrogens are uncertain, because a number of different cell types express estrogen receptors in the peripheral immune system and CNS. Here, we investigated the potential roles of two endogenous CNS cell types in estrogen-mediated neuroprotection. We selectively deleted estrogen receptor alpha or estrogen receptor beta from either neurons or astrocytes using well-characterized Cre-loxP systems for conditional gene knockout in mice and studied the effects of these conditional gene deletions in a well-characterized model of adoptive experimental autoimmune encephalomyelitis (EAE). We found that the pronounced and significant neuroprotective effects of systemic treatment with ERbeta ligand on clinical function, CNS inflammation, and axonal loss during EAE were not completely prevented by conditional deletion of ERbeta from astrocytes or neurons. Interestingly, we found that the pronounced and significant neuroprotective effects of systemic treatment with ERalpha ligand on clinical function, CNS inflammation, and axonal loss during EAE were completely prevented by conditional deletion of ERalpha from astrocytes, whereas conditional deletion of ERalpha from neurons had no significant effect. Given the differential neuroprotective effects of ERalpha ligand treatment versus ERbeta ligand treatment on astrocytes, as well on T-cell and macrophage inflammation, we looked for molecules within astrocytes that were affected by signaling through ERalpha, but not ERbeta. We found that ERalpha ligand treatment, but not ERbeta ligand treatment, decreased expression of the chemokines CCL2 and CCL7 by astrocytes in EAE. Together our data show that neuroprotection in EAE mediated via ERbeta signaling does not require ERbeta on astrocytes or neurons, whereas neuroprotection in EAE mediated via ERalpha signaling requires ERalpha on astrocytes, and not neurons, and reduces astrocyte expression of chemokines that contribute to CNS inflammation. These findings reveal important cellular differences in the neuroprotective mechanisms of estrogen signaling through ERalpha and ERbeta in EAE.