The molecular mechanism of pyroptosis and its related diseases

Abstract

Cells are the basic unit of life, and cell death plays an important role in the body’s metabolism, the occurrence and development of diseases. Pyroptosis is a form of programmed cell death. Pyroptosis is significantly different from other cell death methods (such as apoptosis, necrosis, etc.) in morphological characteristics, occurrence mechanism, and mechanism of action. When a cell undergoes pyroptosis, the nucleus condenses to form a pyroptotic body, numerous pores appear in the cell membrane, the cell swells and ruptures, releasing its contents. Caspase family is a homologous and structurally similar proteolytic enzyme in cytoplasm, which selectively recognizes and cleaves peptide bonds behind downstream target aspartic acid residues. Canspase 1,4,5,11 can induce pyroptosis through different pathways. Besides caspases, gasdermin also plays an important role in pyroptosis. Gasdermins (GSDMs) are a family of functionally diverse proteins expressed in a variety of cell types and tissues. The Gasdermin family includes 6 members, of which gasdermin D is the executor of pyroptosis. Upon cleavage by activated capsese, gasdermen D can be divided into N and C segments. Among them, the N fragment can form pores in the cell membrane, leading to cell swelling, rupture, outflow of cytokines and other contents, triggering the body’s immune response, and leading to pyroptosis. The occurrence of pyroptosis can be divided into the classical pathway and the non-classical pathway. The classical pathway mainly depends on caspase-1, while the non-canonical pathway depends on the activation of Caspase-4/5/11. In addition, there are uncommon Caspase-3/8- mediated pathway and Granzyme-mediated pathway. As a way of cell death, pyroptosis is inextricably linked to disease. Inflammasomes and cytokines produced in the process of pyroptosis can trigger an inflammatory response in the body, and an excessive inflammatory response can lead to diseases, such as infectious diseases, neurological diseases, and tumors. In infectious diseases, pyroptosis is closely related to the infection of a variety of bacteria, fungi and viruses, and PAMPs and LPS can be recognized by corresponding inflammasomes and caspases, respectively, and activate the downstream pyroptotic pathways. Pathogen infection is the main way to induce pyroptosis. In cardiovascular diseases, a high-fat environment can induce an increase in reactive oxygen species (ROS), trigger endothelial cell pyroptosis, and exacerbate the development of atherosclerosis (AS). In the nervous system, cell death is involved in the pathogenesis of the progression of degenerative diseases of the central nervous system, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and stroke. In terms of tumors, pyroptosis can inhibit the occurrence and development of tumors, and at the same time, as a pro-inflammatory death, pyroptosis can form a microenvironment suitable for tumor cell growth, thereby promoting tumor growth.