The Role of RNA Binding Proteins in Inflammation Mediated Reproductive Pathologies
Endometriosis is a major reproductive pathology that affects more than 8.5 million women in North America alone, and 176 million worldwide. It is characterized by the growth of endometrial lining outside of the uterus and remains one of the most important global health challenges due to staggering health care costs, lack of non-invasive diagnostic tests, lack of a cure and significant side effects with current treatments. Recurrent pregnancy loss is another major reproductive pathology, which affects 1-5% of pregnant women worldwide. It is now well established that aberrant inflammation is one of the most important contributing factors in the pathogenesis of these gynecological diseases. RNA binding proteins including Tristetraprolin (TTP) and Human antigen-R (HuR) families are regulators of inflammation, and modulate many hallmark inflammatory cytokines implicated in both endometriosis and RPL, including: tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). To understand the unique contributions of RNA binding protein axis, we screened for TTP/HuR axis in endometriosis patients and investigated functional effects in vitro as well as in a syngeneic mouse model of endometriosis. We also sought out to determine endometrial-endothelial modes of intercellular communication and whether RNA binding proteins are shuttled via extracellular vesicles including exosomes. We report aberrations in the TTP/HuR axis in endometriosis patients and demonstrate that knockdown of TTP in endometriotic epithelial cells yields differential inflammatory cytokine profiles compared to endometrial epithelial cells. We also report for the first time functional effects of endometrial-derived exosomes that participate in a form of intercellular communication with endothelial cells. Further, using a mouse model of RPL, we report downregulation of TTP protein while targets TNF-α and IL-6 are upregulated in placentas treated with Lipopolysaccharide compared to controls. Our results suggest that RNA-binding proteins such as TTP are expressed and involved in the modulation of inflammation-induced pregnancy pathologies. Together, our data demonstrate unique contributions of the HuR/TTP RNA binding protein axis in the pathogenesis of endometriosis and pregnancy loss and opens up a new avenue of research to understand contributions of these RNA binding proteins in modulating inflammatory responses.
URI for this recordhttp://hdl.handle.net/1974/22699
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