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

Oestrogen and oestrogen receptor alpha (ERα) have been implicated in systemic lupus erythematosus pathogenesis. ERα signalling influences dendritic cell (DC) development and function, as well as inflammation and downstream immune responses. We previously reported that ERα modulates multiple Toll‐like receptor‐stimulated pathways in both conventional and plasmacytoid DCs in lupus‐prone mice. For example, CD11chiMHCII+ cell numbers are reduced in mice with global ERα deficiency or when expressing a short variant of ERα. Herein, RNA‐seq analysis of CD11chi cells from bone marrow of NZM2410 mice expressing WT ERα versus ERα short versus ERα 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 ERα 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 ERα is necessary for robust development of DCs, this result suggests that DC fate was determined prior to CD11c expression and subsequent ERα deletion (i.e., proximally in DC ontogeny). Overall, findings point to a clear functional role for ERα in regulating cytokine signalling and inflammation, suggesting that further study into ERα‐mediated regulatory mechanisms in DCs and other immune cell types is warranted. Cytokines and cytokine signaling are profoundly altered in CD11chi immune cells from lupus prone mice expressing different forms of oestrogen receptor alpha (ERα). Heatmaps revealed differentially expressed genes in CD11chi cells that varied depending on multiple parameters: presence of full‐length ERα, presence of a short variant of ERα (missing the AF‐1 domain) and presence of supra‐physiologic oestrogen (in mutant mice, if not ovariectomized). CD11chi cells were derived and sorted from NZM2410 bone marrow cultures treated with GM‐CSF and IL‐4. All cells were stimulated with TLR7/9. Pairwise comparison of WT and ERα null mice only revealed significant differences in IL‐17 and mTOR signaling pathways.