Toll-like receptor 4: A link between “danger signals”, the innate immune system, trophoblast apoptosis and preeclampsia?

Abstract

IMMUNE SYSTEM, TROPHOBLAST APOPTOSIS AND PREECLAMPSIA? YEON MEE KIM, SEO YOUNG OH, JYH KAE NIEN, RICARDO GOMEZ, CHONG JAI KIM, MOSHE MAZOR, VIKKI ABRAHAMS, GIL MOR, SHIGERU SAITO, ROBERTO ROMERO, Wayne State University School of Medicine, Department of Pathology, Detroit, Michigan, Perinatology Research Branch, NICHD, NIH, DHHS, Bethesda, Maryland, CEDIP, Sotero del Rio Hospital, Puente Alto, Chile, Chile, Seoul National University, Seoul, Korea, South Korea, Soroka University Medical Center, Beer Sheva, Israel, Israel, Yale University, Department of Obstetrics and Gynecology, New Haven, Connecticut, Toyama Medical and Pharmaceutical University, Department of Obstetrics and Gynecology, Toyama, Japan, Japan OBJECTIVE: Toll-like receptors (TLRs), discovered to regulate patterning during embryonic development, were subsequently found to play a role in innate immunity. TLRs recognize microbial ligands as well as host products released during tissue damage or ‘‘danger signals’’ (Science 2002;296:301). Engagement of TLR-4 can induce trophoblast cells to produce pro-inflammatory cytokines. Such cytokines may promote trophoblast cell apoptosis, which is increased in preeclampsia. This study was conducted to determine TLR-4 expression patterns in the extravillous trophoblasts (EVT) in the placental bed of women with and without preeclampsia. STUDY DESIGN: Placental bed biopsies were obtained from patients with: (1) normal pregnancy at term (n = 40); (2) severe preeclampsia (n = 15); and (3) preterm delivery and intact membranes (PTD) with and without histologic chorioamnionitis (n = 15 for each group). The expression pattern of TLR-4 in the EVT was examined by double immunohistochemistry. Image analysis was conducted and non-parametric statistics were employed for analysis. RESULTS: (1) The median percentage of TLR-4 positive EVT was significantly higher in patients with preeclampsia than in patients with PTD or normal patients at term (PTD: P = .0001; women at term: P ! .0001). (2) The median percentage of TLR-4 positive EVT was significantly higher in patients with preeclampsia than in those with PTD with histologic chorioamnionitis (P = .0057). (3) The median percentage of TLR-4 positive EVT in the placental bed was significantly higher in patients with PTL and histologic chorioamnionitis than in those without these conditions (P = .037). CONCLUSION: TLR-4 expression is increased in the extravillous trophoblasts in women with preeclampsia. We propose that ‘‘danger signals’’ may increase the expression of TLR-4 by EVT in the placental bed, which might lead to trophoblast apoptosis and defective hemochorional placentation in preeclampsia.