Preeclampsia (PE) is a specific syndrome of human pregnancy, considered the main cause of morbidity and mortality in 2 to 8% of pregnancies worldwide [1], and one of the main causes of maternal death. The clinical parameters that characterize this pathology are arterial hypertension and proteinuria from the twentieth week of pregnancy or in the first days after delivery. However, other maternal dysfunctions may also be related to PE, such as renal failure, liver involvement, neurological or hematological complications, uteroplacental dysfunction, or fetal growth restriction ^[2][3][2,3]. This pathology increases the risk of maternal and fetal mortality, through placental abruption, cerebrovascular events, organ failure, and disseminated intravascular coagulation [4].

Endothelial cells have different functions during non-inflammatory conditions, such as maintaining blood fluidity, regulating blood flow, and maintaining leukocytes in a basal state circulating ^[5][10]. In cases of infection or inflammation, these cells recognize danger signals and they act as active regulators of the inflammatory response ^[5][10], and receptors in these cells help the response to a range of external signals ^[6][11]. This meeting between endothelial cells and danger signals, such as ATP and high mobility group box 1 protein (HMGB1), can activate the NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) ^[7][8][12,13]. Activation of NLRP3 inflammasome in endothelial cells was already observed in animal models, and production of IL-1β by these cells has been shown to contribute to diverse pathological conditions ^[9][10][14,15]. Several recent studies in the literature have demonstrated that women with PE present a significantly higher expression of NLRP3, and related mediators such as caspase-1, IL-1, and IL-18 compared to normotensive healthy pregnant women ^[11][12][13][16,17,18].

2. Preeclampsia and Endothelial Dysfunction

Endothelial dysfunction is the term used to describe an imbalance in these endothelial functions affecting vasoprotective homeostasis ^[14][20].

In normal pregnancies, the typical increase in blood volume is commonly compensated by a slight decrease in blood pressure. For a long time, this rise in blood pressure has been associated with reduced maternal vascular resistance ^[15][16][21,22]. However, in PE, the compensatory maternal vascular adaptations are insufficient, and it has been associated with systemic endothelial dysfunction ^{[17][18][19][20]}[23,24,25,26]. In this syndrome, this characteristic is associated with the PE poorly perfused placenta, which releases proinflammatory and antiangiogenetic factors into maternal circulation ^[21][22][27,28]. This hypothesis has been reinforced by many studies so far. For example, Myers and colleagues demonstrated that healthy myometrium vessels incubated with plasma from PE pregnant women had reduced endothelium mediated vascular relaxation compared to those incubated with plasma from healthy pregnant women ^[23][29]. Plasma from women with PE can modify the endothelial function, altering the balance between vasoactive substances. Despite evidence showing the release of placental factors into maternal circulation could alter endothelial function, the exact mechanism is not fully understood. ^[24][30].

Until today, many studies demonstrated several alterations, both locally and in circulation, in multiple bioactive factors in PE. For example, the angiogenic balance disturbance has been described by decreases in pro-angiogenic vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) by the action of the placental soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) ^{[23][25][26][27]}[29,31,32,33]. Moreover, proinflammatory molecules such as tumor necrosis factor-α (TNF-α), endocan, interleukin-6 (IL-6), and IL-1β have also been reported to be altered in PE ^{[28][29][30][31]}[34,35,36,37]. Altogether, these alterations lead to systemic endothelial dysfunction in PE, and it also is possible that there may be more mechanisms involved that were not discovered yet.

3. NLRP3 Inflammasome Activation and Regulation in Preeclampsia

3.1. Inflammasome Formation and the Role of NLRP3 in the Pathogenesis of PE

The immune response is divided into innate and adaptive immunity. Contact with pathogens or any danger signal activates the innate immune system, as the first line of defense. This process starts quickly as possible to protect the organism and to maintain homeostasis. The immune cells detect the signals from invaders, expressing molecules known as pathogen-associated molecular patterns (PAMPs). Besides that, these cells also identify molecules associated with inflammation and cell death, in cases of sterile inflammation, without any external microbial sign. These molecules associated with inflammation are named damage-associated molecular patterns (DAMPs). PAMPs and DAMPs are recognized by pattern recognition receptors (PRRs). Two of the most studied PRRs are Toll-like receptors (TLRs) and nucleotide-binding domain leucine-rich repeat-containing receptors (NLRs) ^[32][41].

There are 22 recognized members of the NLR family, between them, NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) is the most studied and investigated, because this NLR forms complexes with other proteins, forming multimeric complexes, called inflammasomes ^[33][42].

NLRP3 inflammasome complex is constituted by NLRP3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and the cysteine protease precursor procaspase-1 (Figure 1).

Figure 1. The NLRP3 inflammasome consists of NLRP3, ASC, and caspase-1. NLRP3 is composed of C-terminal leucine-rich repeats (LRRs), a central nucleotide-binding and oligomerization domain (NACHT), and an N-terminal pyrin domain (PYD). ASC is also termed Pycard, containing an N-terminal PYD and a C-terminal caspase recruitment domain (CARD). The last element of the CARD and caspase domains. PAMPs and DAMPs can activate the inflammasome complex and triggers inflammation and pyroptosis.