Placental inflammation by HMGB1 activation of TLR4 at the syncytium

Abstract

Introduction: Normal pregnancy is characterized by an elevated inflammatory state involving the placenta. The placental inflammation is further increased in preeclampsia, resulting in release of harmful danger signals to the maternal circulation. Activation of toll-like receptors (TLR)2 and TLR4 by endogenous danger signals plays a role in inflammatory diseases. Placental TLR2 and TLR4 expression has been reported, and high mobility group box 1 (HMGB1) is a likely endogenous activator of these receptors. We aimed to examine HMGB1 activation of TLR2 and TLR4 as mechanisms of placental inflammation in normal and preeclamptic pregnancies, by combined analysis of expression and function of the ligand HMGB1, the receptors TLR2 and TLR4, and the cytokine responder interleukin (IL)-8.Methods: Protein expression was analyzed in placental tissue from normal and preeclamptic pregnancies, and cytokine responses to two distinct HMGB1 isoforms were examined in placental explants and trophoblasts. Inflammatory and antiangiogenic markers were measured in maternal serum. Results:We demonstrated strong co-localized expression of HMGB1, TLR4 and IL-8 in the syncytium layer of the placenta. Syncytium TLR4 expression and maternal serum levels of IL-8 were significantly increased in preeclamptic compared to normal pregnancies. Functionality was confirmed by TLR4-dependent release of IL-8 from placental explants and trophoblasts in response to the inflammatory isoform of HMGB1.Discussion: This demonstrates a role for the HMGB1-TLR4 pathway at the syncytium layer and suggests involvement in placental inflammation and preeclampsia.

Maternal Obesity and the Uterine Immune Cell Landscape: The Shaping Role of Inflammation

“…Obesity-induced metabolic dysfunction and pregnancy complications share mechanistic similarities. Specifically, proinflammatory factors such as HMGB1 [112][113][114][115], TNF-α [116,117], and IL-1β [118][119][120] play critical roles in the inflammation underlying both obesity and preeclampsia. These key inflammatory mediators when upregulated in obesity [102] may potentiate aberrant maternal inflammation that in turn contribute to the development of pregnancy disorders [121].…”

Hydroxychloroquine may be beneficial in preeclampsia and recurrent miscarriage

“…The above effects of placenta‐induced hypoxia trigger the following maternal responses: (i) a systemic inflammatory response with proinflammatory cytokine production, lysosomal (toll‐like receptor [TLR]2, 4) and extralysosomal (TLR3, 7, 9) TLR activation, alterations in the Th1/Th2 balance, the production of agonistic angiotensin II type 1 receptor antibodies (and hence vasoconstriction via endothelin 1, the stimulation of NADPH oxidase and sFlt1 production) and the activation of the complement system; (ii) the activation of maternal oxidative stress, resulting in endothelial NADPH2 upregulation in women with PE; and (iii) maternal endothelial dysfunction with increased production of vasoconstrictor molecules (endothelin 1, thromboxane A2), increased activation of the renin‐angiotensin system, a decrease in NO, and the overexpression of adhesion molecules (ICAM, VCAM) (leading to the adhesion of monocytes to the endothelium).…”

“…During PE, TLR9 activation is increased due to the presence of nucleic acids from trophoblasts released into the maternal circulation in response to placental hypoxemia . In addition, TLR4 is overexpressed in the syncytium in PE . TLR overexpression disrupts maternal‐fetal immune tolerance.…”

High‐mobility group box 1 is a driver of inflammation throughout pregnancy

“…In circumstances where the placental cells are infected by exogenous ligands, the levels of HMGB1 are increased further illustrating the variety of circumstances where HMGB1 may be a key player in this tissue 31 . Indeed, HMGB1 treatment increases the secretion of the proinflammatory cytokines IL‐6 and IL‐8 through a TLR4‐dependent mechanism in trophoblasts resulting in placenta inflammation 20,32 . Together, these data suggest that sustained placental inflammation caused by HMGB1 could be a driver and potential biomarker for certain placental pathologies.…”