Endogenous and Uric Acid-Induced Activation of NLRP3 Inflammasome in Pregnant Women with Preeclampsia

Abstract

Preeclampsia (PE) is a specific syndrome of pregnancy, characterized by hypertension and proteinuria. This pathology is associated with hyperuricemia and elevated serum levels of inflammatory cytokines. Uric acid crystals may activate an intracellular complex called inflammasome, which is important for processing and release of inflammatory cytokines. This study investigated the state of monocyte activation, both endogenous and stimulated with monosodium urate (MSU), by gene expression of NLRP1 and NLRP3 receptors as well as their association with inflammatory cytokines expression. Monocytes were obtained from peripheral blood of 23 preeclamptic pregnant women, 23 normotensive pregnant women (NT) and 23 healthy non-pregnant women (NP). Inflammasome activation was evaluated by the gene expression of NLRP1, NLRP3, caspase-1, IL-1β, IL-18 and TNF-α by RT-qPCR in unstimulated monocytes (endogenous expression), or after cell stimulation with MSU (stimulated expression). The concentration of cytokines was assessed by ELISA. In preeclamptic pregnant women, gene expression of NLRP1, NLRP3, caspase-1, IL-1β and TNF-α by monocytes stimulated or not with MSU was significantly higher than in NT and NP groups. Stimulation of monocytes from preeclamptic and non-pregnant women with MSU induced increased gene expression of NLRP3, caspase-1 and TNF-α in relation to the endogenous expression in these groups, while this was not observed in the NT group. The cytokine determination showed that monocytes from women with PE produced higher endogenous levels of IL-1β, IL-18 and TNF-α compared to the other groups, while the stimulus with MSU led to higher production of these cytokines in preeclamptic group than in the NT group. In conclusion, the results showed increased basal gene expression of NLRP1 and NLRP3 receptors in monocytes from PE group. These cells stimulation with MSU demonstrates that uric acid plays a role in NLRP3 inflammasome activation, suggesting the participation of this inflammatory complex in the pathogenesis of preeclampsia.

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

“…Information on the action of MSU crystals at the maternal-fetal interface is scarce but it has been published that it does induce IL-1β secretion in a first trimester trophoblast cell line through activation of caspase-1 and of the NLRP3 inflammasome26–28. NLRP3 activation by MSU crystals was also observed in monocytes from PE patients37. This is in line with our current work, wherein we showed the role of caspase-1 in MSU crystals-induced IL-1β secretion in term primary cytotrophoblast cells and placental explants.…”

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

“…Also, IL-1β is a pro-inflammatory cytokine that could contribute to the inflammatory response and disrupts ECs in PE. Monocytes of PE women produce more IL-1β than those of Norm-Preg women (Matias et al, 2015). …”

“…Monocytes treated with PE plasma produce more TNF-α and IL-6 than cells treated with Norm-Preg plasma (Rahardjo et al, 2014). This is likely due to the regulatory effects of IL-10 on monocytes regulating the inflammatory response that occurs during normal pregnancy by controlling TNF-α and IL-1β gene expression (Matias et al, 2015), and this IL-10-mediated regulatory activity could be lost in PE. Interestingly, uric acid is an important stimulator of monocytes to release cytokines, and PE patients often have hyperuricemia.…”

“…Interestingly, uric acid is an important stimulator of monocytes to release cytokines, and PE patients often have hyperuricemia. Also, monocytes from PE patients exhibiting high levels of uric acid produce more TNF-α and IL-1β than those from Norm-Preg women (Matias et al, 2015). …”

The Complement System and Preeclampsia

“…Importantly, a decrease in regulatory T cells is associated with preeclampsia [27], as is intracellular activation of the inflammasome [28, 29]. FoxP3+ regulatory T cells develop in the absence of C5aR1 activation [30].…”