Project 4: The Critical Role of Estrogen in Uterine Macrophage Activation and Function

Director

Patricia A. Pioli, Ph.D.
Assistant Professor
Department of Obstetrics and Gynecology and Microbiology and Immunology

Mission

The human uterine endometrium (EM) is charged with the unique task of maintaining an environment hospitable to implantation and pregnancy, while simultaneously conferring protection against pathogenic challenge. This task is formidable, as more than twenty pathogens may be transmitted through sexual intercourse. The CDC estimates that greater than 19 million new sexually transmitted infections (STIs) occur each year in the United States. STIs are particularly deleterious to women, as women tend to exhibit fewer physical symptoms of disease and therefore may delay seeking treatment. As a result, STIs can compromise women's health and reproductive success. Despite the urgent need for increased understanding of the mechanisms that regulate immunity in the human EM, there is a paucity of data regarding immune defense at this site.

As key phagocytes, macrophages provide both early recognition of pathogens and a crucial bridge between innate and adaptive immunity. While different mucosal tissues have unique roles and encounter different pathogenic challenges, none undergoes the dramatic periodic changes that occur in the uterine EM. We hypothesize that estradiol and the local uterine microenvironment provide a vital influence on uterine macrophage functions. In this regard, we have shown that estradiol pretreatment of human macrophages attenuates pro-inflammatory cytokine production. The overall goal of this project is two-fold: 1) to determine how the uterine micro-environment influences macrophage activation and 2) to determine the molecular mechanism by which estradiol inhibits inflammation in primary human macrophages.

Collectively, these studies will provide key information that will facilitate the development of targeted therapies for the prevention of infection and inflammation at this important mucosal site.

Results

COBRE funding of these studies will facilitate the submission of manuscripts for publication and generate data for subsequent grant submissions.

Publications

Murphy AJ, Guyre PM, Wira CR, Pioli PA. Estradiol regulates expression of estrogen receptor ERα46 in human macrophages. PLoS One. 2009;4(5):e5539.

Hart KM, Murphy AJ, Barrett KT, Wira CR, Guyre PM, Pioli PA. Functional expression of pattern recognition receptors in tissues of the human female reproductive tract. J Reprod Immunol. 2009 Jun;80(1-2):33-40.

Murphy AJ, Guyre PM, Pioli PA. Estradiol suppresses NF-κB activation through coordinated regulation of let-7a and miR-125b in primary human macrophages. J Immunol. 2010 May 1;184(9):5029-37.