Pyroptosis in health and disease

Abstract

The field of cell death has witnessed significant advancements since the initial discovery of apoptosis in the 1970s. This review delves into the intricacies of pyroptosis, a more recently identified form of regulated, lytic cell death, and explores the roles of pyroptotic effector molecules, with a strong emphasis on their mechanisms and relevance in various diseases. Pyroptosis, characterized by its proinflammatory nature, is driven by the accumulation of large plasma membrane pores comprised of gasdermin family protein subunits. In different contexts of cellular homeostatic perturbations, infections and tissue damage, proteases, such as caspase-1 and caspase-4/5 play pivotal roles in pyroptosis by cleaving gasdermins. Gasdermin-D (GSDMD), the most extensively studied member of the gasdermin protein family, is expressed in various immune cells and certain epithelial cells. Upon cleavage by caspases, GSDMD oligomerizes and forms transmembrane pores in the cell membrane, leading to release of pro-inflammatory cytokines. GSDMD-N, the N-terminal fragment, displays an affinity for specific lipids, contributing to its role in pore formation in pyroptosis. While GSDMD is the primary focus, other gasdermin family members are also discussed in detail. These proteins exhibit distinct tissue-specific functions and contribute to different facets of cell death regulation. Additionally, genetic variations in some gasdermins have been linked to diseases, underscoring their clinical relevance. Furthermore, the interplay between GSDM pores and activation of other effectors, such as ninjurin-1 is elucidated, providing insights into the complexity of pyroptosis. The findings underscore the molecular mechanisms that govern pyroptosis and its implications for various physiological and pathological processes.

Exacerbated Activation of the NLRP3 Inflammasome in the Placentas from Women Who Developed Chronic Venous Disease during Pregnancy

“…Abnormal levels of these cytokines have been linked to the presence of hypertension during pregnancy [39], whereas their overexpression in the placenta has been linked to a plethora of obstetric complications [40][41][42]. Also, the formation of active pores due to GSDMD and the release of IL-1β and IL-18 are responsible for a special type of inflammatory cell death named pyroptosis, whose relevance in physiological and pathological conditions is the subject of various studies [43,44]. Enhanced placental pyroptosis has been suggested as a central feature in the pathogenesis of early-onset preeclampsia, leading to the release of different factors into the maternal circulation that contribute to systemic inflammation [45].…”