Pyroptosis and degenerative diseases of the elderly

www.nature.com/cddis REVIEW ARTICLE OPEN Pyroptosis and degenerative diseases of the elderly Jiamin Zhou1,2,3, Jingjing Qiu1,2,3, Yuwan Song1,2,3, Tiantian Liang1,2, Sha Liu1,2, Chao Ren1,2, Xicheng Song ✉ Yan Sun 1,2 1,2 , Limei Cui1,2 ✉ and © The Author(s) 2023 Pyroptosis is a recently described mechanism of programmed cell death mediated by proteins of the gasdermin family. Widely recognized signaling cascades include the classical, non-classical, caspase-3-dependent gasdermin E and caspase-8-dependent gasdermin D pathways. Additional pyroptotic pathways have been subsequently reported. With the rising prevalence of advanced age, the role of pyroptosis in the degenerative diseases of the elderly has attracted increased research attention. This article reviews the primary mechanisms of pyroptosis and summarizes progress in the research of degenerative diseases of the elderly such as presbycusis, age-related macular degeneration, Alzheimer’s disease, intervertebral disc degeneration, and osteoarthritis. 1234567890();,: Cell Death and Disease (2023)14:94 ; https://doi.org/10.1038/s41419-023-05634-1 FACTS ● ● ● Pyroptosis is a recently described mechanism of cell death. Pyroptosis plays a central role in the pathogenesis of degenerative diseases of the elderly. Identification of therapeutic targets in pyroptotic pathways may facilitate the treatment of presbycusis, age-related macular degeneration, Alzheimer’s disease, intervertebral disc disease, and osteoarthritis. INTRODUCTION Programmed cell death (PCD) is an important part of organism development, which plays a crucial role in host resistance to pathogens and maintaining homeostasis. It can be induced by developmental processes and stress inducing signals, such as hormone induction, drug action, oxidative stress, and infection. Several known PCD pathways, including pyroptosis, apoptosis, and necroptosis, are associated with innate immunity [1] (Fig. 1). Apoptosis is the prototypical PCD, which occurs in almost all tissues and is crucial for normal development. Apoptosis is characterized by activation of the caspase family of cysteine proteases. After receiving external or internal pro-apoptotic stimuli, initiating caspases will activate executioner caspases to trigger PCD. When cells contract and divide into apoptotic bodies, they are usually engulfed by surrounding macrophages. Soon thereafter, the apoptosis of a large number of cells may exceed the clearance ability of macrophages, which will exacerbate inflammation and cause host injury [2]. Inhibition of apoptotic caspase-8 in the presence of pro-apoptotic stimuli can trigger necrosis through the serine/threonine protein kinase 1 (RIPK1)—RIPK3 mixed lineage kinase domain (MLKL) axis to induce necroptosis, which is another category of PCD. Necroptosis usually occurs under a variety of pathological conditions, and eventually disrupts the integrity of the plasma membrane, causing release of pro-inflammatory molecules to promote immunemediated injury to surrounding cells [3]. Pyroptosis, also known as inflammatory necrosis, is a type of PCD mediated by gasdermins, and is manifested by the continuous cellular expansion until the rupture of the cell membrane, leading to the release of pro-inflammatory intracellular components [4, 5]. Pyroptosis is the primary cellular response to noxious insults such as pathogen ligands, abnormal levels of host metabolites, and environmental stimuli. Pyroptosis is triggered primarily by a variety of inflammasomes, and is executed by caspases and gasdermin proteins. When inflammasomes are assembled, they trigger caspase activation and then cleave gasdermins to produce toxic fragments that mediate cell membrane perforation [6]. When pyrotosis leads to cell membrane rupture, the release of cytokines such as interleukin-18 (IL-18), interleukin-1β (IL-1 β) and other molecules such as high mobility group protein 1 (HMGB1) and adenosine triphosphate (ATP) promote innate immunity, causing injury to adjacent cells and exacerbation of inflammation [7]. Since first proposed by Brennan et al in 2001, pyroptosis has rapidly become an important research priority in the study of PCD. Pyroptosis plays an important role in the pathogenesis of circulatory [8], respiratory [9], immune [10], digestive [11], and urinary tract disorders [12]. Moreover, the discovery of pyroptosisrelated molecules has identified potential therapeutic targets. With the rising prevalence of advanced age, research on degenerative diseases of the elderly has become increasingly urgent. Abnormalities of the pyroptosis signaling cascade have been observed in the pathogenesis of degenerative diseases of the elderly. This 1 Department of Otolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000 Shandong, PR China. 2Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai 264000 Shandong, PR China. 3These authors contributed equally: Jiamin Zhou, Jingjing Qiu, Yuwan Song. ✉email: ; Edited by Professor Massimiliano Agostini Received: 9 September 2022 Revised: 28 January 2023 Accepted: 30 January 2023 Official journal of CDDpress J. Zhou et al. 2 Fig. 1 Programmed cell death pathways include apoptosis, pyroptosis, and necrosis that occur when cells are subjected to various physiological or pathological stressors. Apoptotic bodies are generally engulfed by macrophages. However, necrosis and pyroptosis compromise cell membrane integrity, causing cytolysis and release of cellular contents. These pro-inflammatory molecules may act as autoantigens; consequent inflammation will injure adjacent normal cells. PYROPTOSIS Molecular pathogenesis of pyroptosis From molecular recognition to cell death, pyroptosis encompasses a variety of molecules and regulates multiple signaling pathways. Inflammasomes are key components of the innate immune response, and play a crucial role in pyroptotic signaling. Inflammasomes are complexes of scaffold proteins that include pattern recognition receptors (PRRs); adaptor proteins/spec-like proteins that contain caspase binding domains (ASCs); and effector proteins such as inflammatory caspases [13]. Pathogen-associated molecular patterns(PAMPs) damage-associated molecular patterns (DAMPs), and altered homeostatic processes (HAMPs) stimulate the oligomerization and activation of PRRs, ASCs, and inflammatory caspases to assemble into inflammasomes [14]. Canonical inflammasomes assembled by NLRP1 [15], NLRP3 [16], NLRC4 [17, 18], AIM2 [19], pyrin [20, 21], and other proteins mediate the classical pyroptotic pathway. Other PRRs, including NLRP6 [22], NLRP7 [23], NLRP9b [24], NLRP12 [25], and IFI16 [26] can also assemble pro-pyroptotic inflammasomes. Under the action of inflammasomes, gasdermin proteins act as key effector molecules of pyroptosis, thereby inciting inflammation and mediating cell death. The gasdermin family has six members: gasdermin (GSDM) A (GSDMA), B (GSDMB), C (GSDMC), (...truncated)