Date of Award

2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Gary Gilkeson

Second Advisor

Wei Jiang

Third Advisor

Amanda C. LaRue

Fourth Advisor

Zihai Li

Fifth Advisor

John Zhang

Abstract

Female lupus prone NZM2410 estrogen receptor alpha (ERα) functionally deficient (ERαKO) mice are protected from renal disease and have prolonged survival compared to wild type (WT) littermates, however the mechanism of protection is unknown. Plasmacytoid dendritic cells (pDCs) and type I interferon (IFN) drive lupus pathogenesis and estrogen acting via ERα enhances both pDC development and IFN production. The objectives for this work were to determine if ERα modulates pDC number, maturation, or function in pre-disease NZM2410 mice as a possible protective mechanism of ERα functional deficiency in lupus prone mice. We measured the effect of ERα functional deficiency on spleen pDC frequency, number, maturation, activation state, and type I IFN activity. ERα functional deficiency reduced the frequency of MHCII+ pDCs without altering overall pDC frequency, number, or maturation state. Additionally, ERαKO NZM2410 mice had significantly decreased numbers of pDCs expressing PDC-TREM, a modulator of toll-like receptor (TLR) mediated IFN production. ERαKO NZM2410 mice also had reduced endogenous spleen type I IFN activity. After in vitro TLR9 stimulation, ERα functional deficiency significantly reduced the expression of PDC-TREM on pDCs from both NZM2410 and C57BL/6 mice. pDCs from ERαKO mice had reduced levels of PDC-TREM transcripts prior to TLR stimulation, suggesting that ERα signaling alters the pDC’s potential to respond to TLR stimulation, thus ‘pre-programming’ the pDCs. Since PDC-TREM is required for pDC TLR mediated IFN production, this finding represents a mechanism by which ERα impacts pDC IFN production. Thus, we have identified a significant effect of ERα functional deficiency on pDCs and type I IFN activity in predisease NZM2410 mice. We believe the modulation of PDC-TREM expression in pDCs and resultant type IFN activity may represent a mechanism by which ERα functional deficiency protects NZM2410 mice from lupus like disease.

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