Conditional knockout of oestrogen receptor alpha in CD11c+ cells impacts female survival and inflammatory cytokine profile in murine lupus

Oestrogen and oestrogen receptor alpha (ER alpha) have been implicated in systemic lupus erythematosus pathogenesis. ER alpha signalling influences dendritic cell (DC) development and function, as well as inflammation and downstream immune responses. We previously reported that ER alpha modulates multiple Toll-like receptor-stimulated pathways in both conventional and plasmacytoid DCs in lupus-prone mice. For example, CD11c(hi)MHCII(+) cell numbers are reduced in mice with global ER alpha deficiency or when expressing a short variant of ER alpha. Herein, RNA-seq analysis of CD11c(hi) cells from bone marrow of NZM2410 mice expressing WT ER alpha versus ER alpha short versus ER alpha null revealed differentially expressed complement genes, interferon-related genes and cytokine signalling (e.g., IL-17 and Th17 pathways). To better understand the role of ER alpha 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 unexpectedly prior to 35 weeks. DC subsets were not significantly different between groups. Since ER alpha is necessary for robust development of DCs, this result suggests that DC fate was determined prior to CD11c expression and subsequent ER alpha deletion (i.e., proximally in DC ontogeny). Overall, findings point to a clear functional role for ER alpha in regulating cytokine signalling and inflammation, suggesting that further study into ER alpha-mediated regulatory mechanisms in DCs and other immune cell types is warranted.