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Role of Pyroptosis in Traumatic Brain and Spinal Cord Injuries

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Role of Pyroptosis in Traumatic Brain and Spinal Cord Injuries Int. J. Biol. Sci. 2020, Vol. 16 2042 Ivyspring International Publisher International Journal of Biological Sciences 2020; 16(12): 2042-2050. doi: 10.7150/ijbs.45467 Review Role of Pyroptosis in Traumatic Brain and Spinal Cord Injuries Xinli Hu1,2*, Huanwen Chen3*, Hui Xu1,2, Yaosen Wu1,2, Chenyu Wu1,2, Chang Jia4, Yao Li1,2, Sunren Sheng1,2, Cong Xu1,2, Huazi Xu1,2, Wenfei Ni1,2, Kailiang Zhou1,2 1. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, China 2. Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China 3. University of Maryland School of Medicine, Baltimore, MD 21201, USA 4. Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, China *These authors contributed equally to this work. Corresponding author: Dr. Wenfei Ni, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 109 West Xueyuan Road, Wenzhou 325000, Zhejiang, China; Tel: +86-577-88002814; E-mail: [email protected]. #Dr. Kailiang Zhou, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 109 West Xueyuan Road, Wenzhou 325000, Zhejiang, China; Tel: +86-577-88002814; E-mail: [email protected] © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2020.02.29; Accepted: 2020.04.05; Published: 2020.04.27 Abstract Central nervous system (CNS) trauma, including traumatic brain injury (TBI) and spinal cord injury (SCI), remains a leading cause for morbidity and mortality worldwide. Past research has shown that cell death plays a critical role in the pathophysiology of CNS injuries. More recently, pyroptosis has been identified as a form of programmed inflammatory cell death, and it is a unique form of cell death in various aspects. Mechanistically, pyroptosis can be categorized into canonical (mediated by caspase-1) and non-canonical (mediated by caspase-4/5/11). In canonical pyroptosis, Nod-like receptors (NLRs) inflammasomes play a critical role, and their activation promotes the maturation and secretion of the inflammatory cytokines interleukin-1β/18 (IL-1β/18), cleavage of gasdermin D (GSDMD), and ultimately pyroptotic cell death. Despite a plethora of new knowledge regarding pyroptosis, detailed understanding of how pyroptosis is involved in CNS injuries and possible ways to improve clinical outcomes following CNS injuries remain elusive. This review discusses the current knowledge on how pyroptosis is involved in CNS injuries, focusing on new discoveries regarding how pyroptosis activation occurs, differences between CNS cell types following injury, time-course of inflammatory responses, and key regulatory steps of pyroptosis. In addition, we highlight various investigational agents that are capable of regulating key steps in pyroptotic cell death, and we discuss how these agents may be used as therapies to improve outcomes following CNS trauma. Key words: Pyroptosis; Traumatic brain injury; Spinal cord injury; Inflammasomes; Cell death Introduction Neurotrauma is one of the most serious 333 and 26 per 100 000 patients per year, respectively. traumatic injuries and is a common cause of long-term Together, TBI and SCI incur an economic burden of disability and death among young adults. Despite approximately 23.7 billion on the American economy clear clinical need, traumatic brain injury (TBI) and ($9.2 billion for TBI, and $14.5 billion for SCI) [1]. spinal cord injury (SCI) are still without adequate Clinically, the treatments of CNS trauma mainly treatments [1]. These devastating injuries not only include methylprednisolone, surgical decompression, impair physical and psychological health, but also supportive medical care, and rehabilitation. However, place financial burdens on families and society. In the patient recovery is limited [2, 3]. While many United States alone, the incidences of TBI and SCI are experimental therapies (mainly involving growth http://www.ijbs.com Int. J. Biol. Sci. 2020, Vol. 16 2043 factors, biomaterials, and cell transplantation etc.) are morphological and biochemical characteristics [18]. being explored in basic and translational research Morphologically, classical findings include cell settings, results have been disappointing [4, 5]. Thus, swelling induced by incoming water molecules, new ideas and therapeutic targets are needed for the formation of pores 10-15 nm in diameter on plasma development of new and effective CNS trauma membranes, and release of pro-inflammatory treatments. cytokines (IL-1β and IL-18) from the cytoplasm [19]. While TBI and SCI share many Biochemically, while apoptotic caspases include pathophysiological features, the complex mechanism initiating apoptotic caspases (caspase-2,8,9,10) and of CNS injury has been a major obstacle for execution apoptotic caspases (caspase-3,6,7), developing treatments [6]. The time course of both pyroptosis caspases include caspases (caspase-1, -4, TBI and SCI include two overall stages. The first stage -5, -11) with both initiator and effector functions [17]. features direct brain or spinal cord tissue damage by Pyroptosis has been extensively observed and external force, which causes cell membrane rupture well-studied in endothelial cells (EC), smooth muscle and results in irreversible cell injury and tissue cells (SMC), phagocytes, macrophages, neurons and necrosis [7, 8]. This is followed by the second stage, astrocytes, as well as various other cell types [20]. In during which cell necrosis induces rapid release of CNS injuries, however, while researchers have intracellular and intra-axonal contents, such as reported evidence of pyroptosis in injured cells, the glutamate, ROS, potassium, and cathepsin B. These mechanisms of pyroptosis and the consequences of substances are highly pro-inflammatory, and thus pyroptosis are less clear. trigger a strong inflammatory response [9]. More The molecular processes of pyroptosis have been specifically, pattern recognition receptors (PRRs) are described previously and is depicted in Figure 1. activated by pro-inflammatory substances released Mechanistically, pyroptosis involves two pathways: from dead cells, thus inducing neuroinflammation the canonical caspase-1 inflammasome pathway, and [10]. Therefore, cell death, and subsequent the non-canonical caspase-4/5/11 inflammasome inflammation, are central biological processes in CNS pathway [21]. In canonical pyroptosis, which centers injury [11]. Classically, three different types of cell around caspase-1, the process is initiated in the death have been widely researched: apoptosis [12], “priming step,” where danger or pathogen-associated autophagic cell death [13], and necrosis [11]. These molecular patterns (DAMPs or PAMPs, respectively) classifications are based largely on morphology, with are recognized by Toll-like receptors (TLRs) and apoptosis featuring cell shrinkage and chromatin Nod-like receptors (NLRs) [22]. Once this occurs, condensation [14], autophagic cell death featuring expression of inflammasome associated genes is cytoplasmic vacuolization, phagocytic uptake and increased, leading to the production of pro-IL-1β and lysosomal degradation [15], and necrosis featuring pro-IL-18. Post-translational modifications can also cell swelling, loss of cell membrane integrity, DNA occur during the priming step of canonical pyroptosis degradation and release of cytoplasmic content [16]. [23]. After the priming step is complete, the process More recently, researchers have identified detailed progresses to the “activation step,” which is centered mechanisms regarding programmed necrotic cell around inflammasome assembly and caspase death, which is characterized as mitochondrial activation [24]. Here, pro-caspase-1 and adaptor permeability transition (MPT) dependent necrosis, protein apoptosis-associated speck like proteins necroptosis, ferroptosis, and pyroptosis [17]. Among (ASC) are recruited (often by nod-like receptor family these novel mechanisms, accumulating evidence pyrin domain containing 3 (NLRP3)) to form suggests a critical role of pyroptosis, a process of inflammasomes. After that, pro-caspase-1 is cleaved programmed inflammatory cell death, in CNS to form caspase-1, which not only promotes cleavage trauma. In this review, we summarize recent studies of pro-IL-1β/18 but also cleaves GSDMD into two of pyroptosis in CNS injuries, which have begun to fragments [25]. The N-terminal fragment forms elucidate how pyroptosis is involved in CNS trauma 10-15nm pores in the cell membrane, which and how its regulation may be used as potential novel eventually leads to discharge of inflammatory factors, neuroprotective treatments. cell swelling, membrane rupture [26]. Overall, caspase-1 can be activated by various Overview of Pyroptosis inflammasomes including nod-like receptors (NLRs), Pyroptosis was first termed in 2002, and it was AIM2-like receptors (ALRs) [27], or tripartite motif first observed in macrophages that underwent a family (TRIM). Among these, nucleotide-binding unique caspase-1-programmed cell death following oligomerization domain (NOD)-like receptor (NLR) exposure to Salmonella. Pyroptosis is different from family have been extensively researched,
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