Understanding a Potential Role for the NLRP3 Inflammasome in Placenta-Mediated Pregnancy Complications

Abstract

Stillbirth affects approximately 2 million pregnancies annually and is closely linked to placental dysfunction, which may also present clinically as foetal growth restriction (FGR) or pre-eclampsia (PE). Placental dysfunction can arise from a range of insults, including the inflammatory conditions villitis of unknown aetiology (VUE) and chronic histiocytic intervillositis (CHI). Despite ample research regarding the pathophysiology of placental dysfunction, the literature surrounding placental inflammation is more limited, with no currently established treatments. In the absence of infection, placental inflammation is hypothesised to be stimulated by damage-associated molecular patterns (DAMPs), known as sterile inflammation. The NLRP3 inflammasome, a protein scaffold that unites within the cytosol of cells, is a proposed contributor. The NLRP3 inflammasome is dysregulated in numerous diseases and has shown evidence of activation through the sterile inflammatory pathway via DAMPs. Studies have demonstrated the upregulation of the NLRP3 inflammasome and its components in placentally-mediated pregnancy pathologies. However, the link between placental dysfunction seen in these disorders and the NLRP3 inflammasome is not yet firmly established. This manuscript aims to review the evidence regarding placental inflammation seen with placental dysfunction, discuss its association with the NLRP3 inflammasome, and identify potential therapeutic interventions for this pathological inflammatory response.

Keywords: DAMPs; NLRP3 inflammasome; chronic histiocytic intervillositis; foetal growth restriction; sterile inflammation; villitis of unknown aetiology.

FIGURE 1

The different pathways cellular stressors act through to cause NLRP3 inflammasome priming and activation, including the specific DAMPs they stimulate and the associated receptors they bind to. This diagram summarises information from various publications [55, 56, 57, 58, 59, 60, 61, 62]. Figure created using Mural diagramming software.

FIGURE 2

The structure of the NLRP3 trimeric protein and the components of the NLRP3 inflammasome complex. The stimuli for the priming and activation phase, as well as the subsequent downstream signalling events following NLRP3 inflammasome formation are shown. The products resulting from NLRP3 inflammasome activation are also depicted.