Examining Sexual Dimorphisms: The Role of Estradiol Signaling in Modulating Immunity

Description (Research Summary for parent award): Sexual dimorphisms associated with immunity and autoimmunity are well described. In some instances, these differences have been attributed in part to estradiol or androgen hormone production and signaling; however, while mechanistic data relating steroids to immune function are emerging, there are still significant gaps in our knowledge. Our lab has become interested in estrogen effects on the immune system, specifically on innate immunity, as a result of our work on an unusual disease called lymphangioleiomyomatosis (LAM). LAM is a rare cystic lung disease found almost exclusively in women. The cystic lung changes are caused by small multifocal smooth muscle cell clusters in the lungs that contain mutations in one of the two tuberous sclerosis (TSC) genes. In patients, LAM is highly estrogen sensitive, as it worsens with puberty, pregnancy, and oral contraception, and stabilizes after menopause. To explain the remarkable female predominance of LAM, as well as its estrogen sensitivity, we proposed that LAM smooth muscle cells in the lungs may originate from the myometrium of the uterus. In fact, when we knocked out TSC2 expression in the uterus, all mice developed aggressive myometrial growth that resembled LAM, with 50% developing lung myometrial nodules from the uterus later in life. Mouse TSC2-null uteri were highly sensitive to estradiol, as growth was eliminated with oophorectomy or aromatase inhibitor treatment. In contrast, isolated LAM cells from these mouse uteri, as well as other TSC2-null cells, had little estradiol sensitivity in-vitro, suggesting that, in-vivo, estradiol promotes LAM progression indirectly. Preliminary data confirm that in fact estradiol via ERa stimulates innate immunity in mice by promoting polymorphonuclear (PMN) cell production in the bone marrow. We have further shown that PMNs stimulate TSC2-null myometrial cell growth in large part through the release of neutrophil elastase (NE). Here we propose to examine the mechanisms by which estradiol enhances PMN production in the bone marrow, as well as how estradiol and PMNs act locally within the TSC2-null myometrium to promote LAM progression. This work will uncover novel mechanisms of estradiol-mediated changes in innate immunity that will apply to all aspects of biology, from tumor physiology to infectious diseases to autoimmunity.