Uric Acid Crystals Induce Placental Inflammation and Alter Trophoblast Function via an IL-1–Dependent Pathway: Implications for Fetal Growth Restriction

Abstract

Excessive placental inflammation is associated with several pathological conditions, including stillbirth and fetal growth restriction (FGR). While infection is a known cause of inflammation, a significant proportion of pregnancies have evidence of inflammation without any detectable infection. Inflammation can also be triggered by endogenous mediators, called damage associated molecular pattern (DAMPs) or alarmins. One of these DAMPs, uric acid is increased in the maternal circulation in pathological pregnancies and is a known agonist of the Nlrp3 inflammasome and inducer of inflammation. However its effects within the placenta and on pregnancy outcome remain largely unknown. We found that uric acid crystals (monosodium urate, MSU, crystals) induces a pro-inflammatory profile in isolated human term cytotrophoblast cells, with a predominant secretion of IL-1β and IL-6, a result confirmed in human term placental explants. Pro-inflammatory effects of MSU crystals were shown to be IL-1-dependent using a caspase-1 inhibitor (inhibits IL-1 maturation) and IL-1Ra (inhibits IL-1 signaling). The pro-inflammatory effect of MSU crystals was accompanied by trophoblast apoptosis and decreased syncytialisation. Correspondingly, administration of MSU crystals to rats during late gestation induced placental inflammation and was associated with fetal growth restriction. These results make a strong case for an active pro-inflammatory role of MSU crystals at the maternal-fetal interface in pathological pregnancies, and highlight a key mediating role of IL-1. Furthermore, our study describes a novel in vivo animal model of non-infectious inflammation during pregnancy, which is triggered by MSU crystals and leads to reduced fetal growth.

Placental inflammation in pre-eclampsia by Nod-like receptor protein (NLRP)3 inflammasome activation in trophoblasts

“…Our in‐vitro studies in placental explants and trophoblasts confirmed functional activity of the NLRP3 inflammasome pathway. This is the first study demonstrating cholesterol crystal‐mediated NLRP3 activation in trophoblasts, as inflammasome responses have only been shown previously for uric acid, ATP and nigericin in these cells . NLRP3 inflammasome activation requires an already exaggerated inflammatory setting, as a priming signal is needed to achieve sufficient intracellular levels of NLRP3 and pro‐IL‐1β .…”

“…PRR activation in preeclampsia may be induced by factors derived from maternal serum and/or within the stressed placental tissue. It has been reported that maternal serum levels of cholesterol and uric acid are elevated in pre-eclampsia and FGR [21][22][23][24][25][26][27][28], that cholesterol is accumulated in pre-eclamptic placentas [29] and that uric acid crystals activate the NLRP3 inflammasome in human placentas [30]. Trophoblast NLRP3 activation has been assigned a role in pre-eclampsia development [31][32][33][34].…”

Uric acid increases cellular and humoral alloimmunity in primary human peripheral blood mononuclear cells

“…Thus hyperuricaemia may be detrimental for graft survival by enhancing both cellular and humoral alloimmunity, especially during periods with relatively low blood levels of immunosuppressive medications. It is interesting that in the case of the naturally successful semi‐allogenic pregnancy increased urate levels have been associated with adverse events, such as preeclampsia and foetal growth retardation; and a recent study has shown that urate crystals cause NLRP3‐inflammasome and IL‐1β‐mediated placental inflammation and dysfunction leading to foetal growth retardation …”

“…It is interesting that in the case of the naturally successful semi-allogenic pregnancy increased urate levels have been associated with adverse events, such as preeclampsia and foetal growth retardation; and a recent study has shown that urate crystals cause NLRP3-inflammasome and IL-1β-mediated placental inflammation and dysfunction leading to foetal growth retardation. 27 Another more convincing study about the role of uric acid in triggering alloimmunity is derived from the field of bone marrow transplantation. In an experimental blood marrow transplantation, intestinal commensal bacteria and uric acid contribute to NLRP3-inflammasome-mediated IL-1β production, while gastrointestinal decontamination and uric Fig.…”

Dose‐dependent structural and immunological changes in the placenta and fetal brain in response to systemic inflammation during pregnancy

“…Maternal inflammation is detrimental for the developing fetal brain and can result in lifelong complications for surviving children, including cerebral palsy, autism spectrum disorder, and schizophrenia 4,10‐12 . Infections account for 20%‐30% of all causes of preterm birth and are a well‐known cause of inflammation‐induced fetal brain injury 13‐23 . The remaining preterm births and fetal brain injuries have no detectable infectious origin, suggesting that inflammation may be involved 24‐27 …”