Conditional knockout of ERa in CD11c+ cells, impact on survival and inflammatory cytokines in murine lupus

Estrogen and estrogen receptor alpha (ERa) have been implicated in systemic lupus erythematosus (SLE) pathogenesis. ERa signaling influences B cell and dendritic cell (DC) development and function, as well as inflammation and downstream immune responses. We previously reported that ERa modulates TLR-stimulated inflammatory pathways in conventional and plasmacytoid DCs in lupus-prone mice. CD11chiMHCII+ cell numbers are reduced in mice with global ERa deficiency or when expressing a short variant of ERa. RNA-seq analysis in CD11chi cells from bone marrow of NZM2410 mice expressing WT ERa vs. an ERa short (AF-1 mutant) vs. ERa null, revealed differentially expressed complement genes, interferon-related genes and cytokine signaling (e.g., IL-17 and Th17 pathways). Cytokine levels varied among different genotypes, demonstrating the complex nature of ERa regulation. To better understand the role of ERa in CD11c+ cells, lupus prone NZM2410 mice with selective deletion of the Esr1 gene in CD11c+ cells were generated. Phenotype and survival of these mice were similar with the exception of Cre positive (CrePos) female mice. CrePos females, but not males, all died prior to 35 weeks. Surprisingly, DC populations were not significantly different between groups. Since ERa is necessary for optimal development of most DC subsets, this result suggests that DC fate was determined prior to CD11c expression and subsequent ERa deletion (i.e. proximally in DC ontogeny). Overall, findings point to a clear functional role for ERa in regulating cytokine signaling and inflammation, suggesting that further study into ERa-mediated regulatory mechanisms in DCs is warranted. Overall design: RNA-seq analysis in CD11chi cells from bone marrow of NZM2410 mice expressing wild type (WT) estrogen receptor alpha (Era) vs. an ERa short (AF-1 mutant) vs. ERa null.