Background/Purpose

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that affects women at a 9 to 1 ratio compared to men. To further understand mechanisms underlying the female predominance our laboratory is investigating the role of estrogen receptor alpha (ERα) in SLE disease development. In lupus-prone mice, absence of hormone responsive ERα increased survival and decreased glomerulonephritis despite no effect on autoantibody production or renal immune complex deposition. To explain this protective effect, we hypothesized ERα deficiency impacts innate immune responses and in particular plasmacytoid dendritic cell (pDC) function. Our previous work showed ERα deficiency reduced the bone marrow derived dendritic cell (DC) toll-like receptor (TLR) mediated type I Interferon response. To determine the significance of the reduced dendritic cell interferon response in disease development we investigated the impact of ERα deficiency on spleen pDC activation state ex vivo in pre-disease lupus-prone mice.  

Methods

We measured the number, maturation state, and activation state of pDCs ex vivo from the spleens of pre-disease (12 to 14 week old) WT and hormone responsive ERα deficient female lupus-prone mice (NZM2410) using flow cytometry. pDCs were identified as singlets, live, CD11b^–B220⁺SiglecH⁺. Activation markers measured included MHC class lI, CD40, and pDC-TREM. Ly49Q expression was used as the marker to identify fully mature pDCs. We also measured activation of the bone marrow derived pDCs, sorted as live, CD11b^–, B220⁺, and CD11c⁺, after TLR 9 stimulation in vitro. 

Results

ERα deficiency reduced the activation state of spleen pDCs from pre-disease lupus-prone mice. The frequency of spleen pDCs expressing the activation markers MHC class II and pDC-TREM was reduced by ERα deficiency (n=20, p=0.002, p=0.06). This finding was specific to lupus-prone prone mice. We did not detect any alteration in the frequency of activated pDCs between WT and ERα deficient age and sex matched C57BL/6 mice. To determine if the reduced frequency of activated pDCs was the result of ERα deficiency mediated alterations in pDC maturation or Toll-like receptor (TLR) responsiveness, we measured pDC maturation state ex vivo and TLR responsiveness in vitro in pDCs from WT and ERα deficient lupus-prone mice. ERα deficiency did not affect the maturation state of spleen pDCs, as measured by Ly49Q expression. However, ERα deficiency reduced TLR 9 mediated activation of bone marrow derived pDCs. After stimulation with TLR 9 ligand, a greater frequency of pDCs from WT mice expressed MHC class II and pDC-TREM compared to ERα deficient pDCs (n=8, p=0.002, p=0.002). 

Conclusion

Our findings suggest the absence of hormone responsive ERα reduces in vivo pDC activation state by impairing pDC responsiveness to TLR ligands in lupus-prone mice. These findings may explain the protective role of hormone responsive ERα deficiency in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/absence-of-hormone-responsive-estrogen-receptor-alpha-reduces-the-activation-of-plasmacytoid-dendritic-cells-in-lupus-prone-mice/