Toll-like receptors in placental tissue from women with and without complication of preeclampsia in pregnancy
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Human pregnancy is characterized by a mild systemic inflammatory response that is essential for maternal metabolic adaptation and immunological tolerance to the semiallogeneic fetus. Trophoblasts are the placental cells in direct contact with the maternal blood, thus being of major importance for interaction between mother and fetus. Villous trophoblasts exhibit innate immune cells properties, such as expression of Toll-like receptors (TLRS) and release of proinflammatory cytokines. Expression of TLRs enables trophoblasts to modulate immune response against invading pathogens. These receptors also provide the tools to respond to danger signals and promote inflammatory response, which is important for physiological functions, but may also have damaging consequences. For instance, impaired placentation results in placental oxidative stress, triggering release of cytokines and placental debris to the maternal circulation. This increased proinflammatory response is involved in the pathogenesis of preeclampsia. Increased knowledge on the role of trophoblasts in this abnormal inflammatory response will provide a better understanding of the disease pathophysiology. In this study we approached the subject by comparing the expression of TLR2 and TLR4 and their ligand high-mobility group box 1 (HMGB1) in placental villi, both in placentas from normal pregnancies and pregnancies complicated with preeclampsia. Immunohistochemical study was performed to identify different cells types, through staining for specific cellular markers, and to detect expression of TLR2, TLR4 and HMGB1. Staining for CD31 and CD45 identified fetal endothelial cells and leucocytes, respectively, and were used to guide cellular localization in slides stained for TLR2, TLR4 and HMGB1. Interestingly, we found that fetal endothelial cells and Hofbauer cells (placental macrophages) highly expressed TLR2, TLR4 and HMGB1, both in normal and pathological placentas, suggesting a role in innate immune response. Trophoblasts were identified through CK7 immunostaining. Although our study did not detect expression of TLR2 in trophoblasts, expression of TLR4 and HMGB1 was observed both in normal and preeclamptic placentas. We also used a novel automated approach, which greatly diminishes examiner subjectivity, to measure the expression of TLR4 and HMGB1. We were able to show a significantly increased expression of both TLR4 and HMGB1 in preeclampsia. Cytoplasmic expression of HMGB1 suggests that trophoblasts are activated and able to release the protein. HMGB1 may increase expression of TLR4 and, thus, increase its own production, leading to a positive feedback loop that might be involved in the exaggerated inflammatory response seen in preeclampsia.