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.
Highlights
Preeclampsia (PE) is a specific syndrome of human pregnancy, and the leading cause of morbidity, mortality and premature delivery between 2 and 7% of pregnancies [1]
Considering that high levels of uric acid are often observed in pregnancies complicated by PE, and are associated with oxidative stress and elevated levels of IL-1β and TNF-α produced by monocytes, the present study aimed to evaluate the role of NLRP1 and NLRP3 inflammasomes in endogenous or monosodium urate-induced activation of monocytes from pregnant women with PE
The results of the present study show higher gene expression of NLRP1 and NLRP3 receptors, caspase-1 as well as IL-1β, IL-18 and TNF-α in peripheral blood monocytes of pregnant women with PE
Summary
Preeclampsia (PE) is a specific syndrome of human pregnancy, and the leading cause of morbidity, mortality and premature delivery between 2 and 7% of pregnancies [1]. Monocytes from women with PE are endogenously activated and release significantly higher concentrations of tumor necrosis factor alpha (TNF-α), superoxide anion and hydrogen peroxide compared to monocytes from normotensive pregnant women. These results confirm that PE is characterized by oxidative stress and that maternal circulating monocytes may represent an important source of free radicals and cytokines during the inflammatory disease [11,14]. We reported that monocytes from women with PE are classically activated and produce higher levels of the inflammatory cytokines TNF-α and IL-12 associated with higher expression of TLR4 and CD64 surface markers. These results provide evidence that the systemic inflammatory environment in PE may differentiate and polarize the monocytes to the M1 phenotype [17]
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