Placental Toll-Like Receptor 3 and Toll-Like Receptor 7/8 Activation Contributes to Preeclampsia in Humans and Mice

Abstract

Preeclampsia (PE) is a pregnancy-specific hypertensive syndrome characterized by excessive maternal immune system activation, inflammation, and endothelial dysfunction. Toll-like receptor (TLR) 3 activation by double-stranded RNA (dsRNA) and TLR7/8 activation by single-stranded RNA (ssRNA) expressed by viruses and/or released from necrotic cells initiates a pro-inflammatory immune response; however it is unknown whether viral/endogenous RNA is a key initiating signal that contributes to the development of PE. We hypothesized that TLR3/7/8 activation will be evident in placentas of women with PE, and sufficient to induce PE-like symptoms in mice. Placental immunoreactivity and mRNA levels of TLR3, TLR7, and TLR8 were increased significantly in women with PE compared to normotensive women. Treatment of human trophoblasts with the TLR3 agonist polyinosine-polycytidylic acid (poly I:C), the TLR7-specific agonist imiquimod (R-837), or the TLR7/8 agonist CLO97 significantly increased TLR3/7/8 levels. Treatment of mice with poly I:C, R-837, or CLO97 caused pregnancy-dependent hypertension, endothelial dysfunction, splenomegaly, and placental inflammation. These data demonstrate that RNA-mediated activation of TLR3 and TLR7/8 plays a key role in the development of PE.

Functional Toll-like receptors in primary first trimester trophoblasts

“…induces murine miscarriage and PTB, and PE-like symptoms in rodents (Tinsley et al, 2009, Chatterjee et al, 2012, Koga et al, 2009. Combined with our findings, it is reasonable to assume that infectious or cell stress-related TLR3 activation in early gestational trophoblasts might have harmful consequences.…”

“…Enhanced placental expression of endosomal TLRs in PTB and PE in humans have been shown (Chatterjee et al, 2012, Pineda et al, 2011. Viruses such as cytomegalovirus may infect and replicate in the placenta inducing local TLR3-mediated inflammation (Tabeta et al, 2004), and 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 18 RNA released from damaged tissue or contained within endocytosed cells are endogenous TLR3…”

“…Reports of trophoblast TLR expression suggest a role in placentation and inflammatory responses during pregnancy, but the majority of existing studies have examined placental tissue (Holmlund et al, 2002, Klaffenbach et al, 2005, Pineda et al, 2011, Chatterjee et al, 2012 or term trophoblasts (Chan and Guilbert, 2006, Mitsunari et al, 2006, Aye et al, 2012, Lucchi and Moore, 2007, Ma et al, 2006, Ma et al, 2007. TLR2, TLR4…”

“…Functional TLR studies related to first trimester have largely been conducted on trophoblast cell lines (Abrahams et al, 2004, Klaffenbach et al, 2005, Mulla et al, 2013, Komine-Aizawa et al, 2008, Nakada et al, 2009, Chatterjee et al, 2012, and in primary first trimester trophoblasts, TLR3 and TLR4 activated release of the pro-inflammatory cytokines IL-6, IL-8 and IFN-β has been reported (Abrahams et al, 2005, Anton et al, 2012, Wang et al, 2011. Collectively, these findings indicate that TLR-mediated trophoblast activation is of importance in pregnancy, but the knowledge is limited and the functional role of TLRs in early gestational trophoblasts has yet to be established.…”

Transmissão materno-fetal do HIV-1: efeito da sinalização via TLR7/8 na ativação de células dendríticas para produção de resposta anti-viral em mães infectadas por HIV-1 e seus recém-nascidos.

“…A quantificação de TLR8 evidencia maior expressão deste receptor tanto no vilo, especificamente no sinciotrofoblasto, quanto na decídua de mães infectadas comparado às mães saudáveis. Em casos de gestantes com pré-eclâmpsia também é identificado maior expressão de TLR8 na decídua (CHATTERJEE et al, 2012). O quadro de pré-eclâmpsia pode repercutir na produção excessiva de tecido em necrose, apoptose anormal durante a implantação e remodelamento de artérias em espiral presentes na placenta, levando ao aumento da expressão dsRNA (dupla fita de RNA) e ssRNA (simples fita de RNA) (CHATTERJEE et al, 2012).…”