| First Author | Cunningham MA | Year | 2019 |
| Journal | J Autoimmun | Volume | 97 |
| Pages | 59-69 | PubMed ID | 30416032 |
| Mgi Jnum | J:295604 | Mgi Id | MGI:6454106 |
| Doi | 10.1016/j.jaut.2018.10.011 | Citation | Cunningham MA, et al. (2019) Novel mechanism for estrogen receptor alpha modulation of murine lupus. J Autoimmun 97:59-69 |
| abstractText | Female sex is a risk factor for lupus. Sex hormones, sex chromosomes and hormone receptors are implicated in the pathogenic pathways in lupus. Estrogen receptor alpha (ERalpha) knockout (KO) mice are used for defining hormone receptor effects in lupus. Prior studies of ERalpha KO in lupus have conflicting results, likely due to sex hormone levels, different lupus strains and different ERalpha KO constructs. Our objective was to compare a complete KO of ERalpha vs. the original functional KO of ERalpha (expressing a short ERalpha) on disease expression and immune phenotype, while controlling sex hormone levels. We studied female lupus prone NZM2410 WT and ERalpha mutant mice. All mice (n = 44) were ovariectomized (OVX) for hormonal control. Groups of each genotype were estrogen (E2)-repleted after OVX. We found that OVXed NZM mice expressing the truncated ERalpha (ERalpha short) had significantly reduced nephritis and prolonged survival compared to both wildtype and the complete ERalphaKO (ERalpha null) mice, but surprisingly only if E2-repleted. ERalpha null mice were not protected regardless of E2 status. We observed significant differences in splenic B cells and dendritic cells and a decrease in cDC2 (CD11b+CD8(-)) dendritic cells, without a concomitant decrease in cDC1 (CD11b-CD8a+) cells comparing ERalpha short to ERalpha null or WT mice. Our data support a protective role for the ERalpha short protein. ERalpha short is similar to an endogenously expressed ERalpha variant (ERalpha46). Modulating its expression/activity represents a potential approach for treating female-predominant autoimmune diseases. |
