Complete knockout of estrogen receptor alpha is not directly protective in murine lupus

Systemic lupus erythematosus (SLE) is a chronic and potentially severe autoimmune disease that disproportionately affects women. Despite a known role for hormonal factors impacting autoimmunity and disease pathogenesis, the specific mechanisms of action remain poorly understood. Our laboratory previously backcrossed estrogen receptor alpha knockout (ER alpha KO) mice onto the NZM2410 lupus prone background to generate NZM/ER alpha KO mice. This original ERaKO mouse, developed in the mid-1990s and utilized in hundreds of published studies, is not in fact ER alpha null. They express an N-terminally truncated ER alpha, and are considered a functional KO. They have physiologic deficiencies including infertility due to disruption of a critical activation domain (AF-1) at the N terminus of ER alpha, required for most classic estrogen (E2) actions. We demonstrated that female NZM/ER alpha KO mice had significantly less renal disease and significantly prolonged survival compared to WT littermates despite similar serum levels of autoantibodies and glomerular immune complex deposition. Herein, we present results of experiments using a lupus prone true ER alpha-/- mice (deletional KO mice on the NZM2410 background), surprisingly finding that these animals were not protected if they were ovariectomized, suggesting that another hormonal component confers protection, possibly testosterone, rather than the absence of the full-length ERa. (C) 2017 Elsevier Inc. All rights reserved.