Role of the NLRP3 Inflammasome in Preeclampsia

Abstract

Reproduction involves tightly regulated series of events and the immune system is involved in an array of reproductive processes. Disruption of well-controlled immune functions leads to infertility, placental inflammation, and numerous pregnancy complications, including preeclampsia (PE). Inflammasomes are involved in the process of pathogen clearance and sterile inflammation. They are large multi-protein complexes that are located in the cytosol and play key roles in the production of the pivotal inflammatory cytokines, interleukin (IL)-1β and IL-18, and pyroptosis. The nucleotide-binding oligomerization domain, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasome is a key mediator of sterile inflammation induced by various types of damage-associated molecular patterns (DAMPs). Recent evidence indicates that the NLRP3 inflammasome is involved in pregnancy dysfunction, including PE. Many DAMPs (uric acid, palmitic acid, high-mobility group box 1, advanced glycation end products, extracellular vesicles, cell-free DNA, and free fatty acids) are increased and associated with pregnancy complications, especially PE. This review focuses on the role of the NLRP3 inflammasome in the pathophysiology of PE.

Keywords: NLRP3 inflammasome; inflammation; interleukin-1β; preeclampsia; pregnancy.

Figure 1

Schematic mechanisms of NLRP3 inflammasome activation. NLRP3 is activated by various endogenous DAMPs: uric acid crystals (MSU), cholesterol crustal, cell-free DNA (cfDNA), high-mobility group box 1 (HMGB1), extracellular debris, extracellular vesicles (EVs), advanced glycation end-products (AGEs), and free fatty acid. Various events such as intracellular ATP release, NLRP3 deubiqutination, relocalization, reactive oxygen species (ROS) generation, mitochondrial dysfunction, lysosome rapture, and cathepsin release occur depending on the effects of damage-associated molecular patterns (DAMPs). Then, inflammasome components, including NLRP3, ASC, and procaspase-1, form the NLRP3 inflammasome complexes. Finally, activated caspase-1 induces the inflammatory form of cell death known as pyroptosis and cleaves the precursor cytokines pro-IL-1β and pro-IL-18, generating the biologically active cytokines IL-1β and IL-18.

Figure 2

Concept of association of NLRP3 inflammasome in pathogenesis of pregnancy complications. Maternal risk such as hypertension and obesity are associated with the elevation of damage-associated molecular patterns (DAMPs). DAMPs activate NLRP3 inflammasome, accumulate immune cells, and induce inflammatory cytokine production and vascular dysfunction in placenta. These events result in placental inflammation and dysfunction, leading to pregnancy complications, such as preeclampsia, spontaneous abortion, recurrent pregnancy loss, and fetal growth restriction.