Roles of the pyroptosis signaling pathway in a sepsis-associated encephalopathy cell model

Wang, Yan; Liu, Xueyan; Wang, Qiang; Yang, Xin

doi:10.1177/0300060520949767

Cited by 11 publications

(6 citation statements)

References 35 publications

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“…[53,[63][64][65][66][67][68][69][70][71][72]. Pyroptosis has been proved to be closely related to sepsis-induced organ damage, but whether inhibiting pyroptosis could be a possible therapy tactic for the brain in sepsis is starved for more evidence [73,74]. In this study, we focus on exploring the candidate molecules or pathways that could regulate pyroptosis.…”

Section: Discussionmentioning

confidence: 99%

HSF1 Alleviates Brain Injury by Inhibiting NLRP3-Induced Pyroptosis in a Sepsis Model

et al. 2023

Mediators of Inflammation

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Background. Sepsis, which could cause a systemic inflammatory response, is a life-threatening disease with a high morbidity and mortality rate. There is evidence that brain injury may be related to severe systemic infection induced by sepsis. The brain injury caused by sepsis could increase the risk of mortality in septic patients, which seriously affects the septic patient’s prognosis of survival. Although there remains a focus on sepsis research, clinical measures to prevent and treat brain injury in sepsis are not yet available, and the high mortality rate is still a big health burden. Therefore, it is necessary to investigate the new molecules or regulated pathways that can effectively inhibit the progress of sepsis. Objective. NLR family pyrin domain-containing 3 (NLRP3) increased in the procession of sepsis and functioned as the key regulator of pyroptosis. Heat shock factor 1 (HSF1) can protect organs from multiorgan dysfunction syndrome induced by lipopolysaccharides in mice, and NLRP3 could be inhibited by HSF1 in many organs. However, whether HSF1 regulated NLRP3 in sepsis-induced brain injury, as well as the detailed mechanism of HSF1 in brain injury, remains unknown in the sepsis model. In this research, we try to explore the relationship between HSF1 and NLRP3 in a sepsis model and try to reveal the mechanism of HSF1 inhibiting the process of brain injury. Methods. In this study, we used wild-type mice and hsf1-/- mice for in vivo research and PC12 cells for in vitro research. Real-time PCR and Western blot were used to analyze the expression of HSF1, NLRP3, cytokines, and pyrolytic proteins. EthD-III staining was chosen to detect the pyroptosis of the hippocampus and PC12 cells. Results. The results showed that HSF1 is negatively related to pyroptosis. The pyroptosis in cells of brain tissue was significantly increased in the hsf1-/- mouse model compared to hsf1+/+ mice. In PC12 cells, hsf1 siRNA can upregulate pyroptosis while HSF1-transfected plasmid could inhibit the pyroptosis. HSF1 could negatively regulate the NLRP3 pathway in PC12 cells, while hsf1 siRNA enhanced the pyroptosis in PC12 cells, which could be reversed by nlrp3 siRNA. Conclusion. These results imply that HSF1 could alleviate sepsis-induced brain injury by inhibiting pyroptosis through the NLRP3-dependent pathway in brain tissue and PC12 cells, suggesting HSF1 as a potential molecular target for treating brain injury in sepsis clinical studies.

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Section: Discussionmentioning

confidence: 99%

HSF1 Alleviates Brain Injury by Inhibiting NLRP3-Induced Pyroptosis in a Sepsis Model

et al. 2023

Mediators of Inflammation

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“…Similarly, in the noncanonical pathway, cytosolic LPS is sensed by casepase-4/5/ 11, which are in turn activated and cleave GSDMD into GSDMD-NT. In sepsis, both pathways can be activated (134). The NOD-like receptor and pyrin domain containing 3 (NLRP3) is one of the most-explored inflammasomes involved in the canonical pathway (135).…”

Section: Neuronal Lossmentioning

confidence: 99%

Current Understanding of Long-Term Cognitive Impairment After Sepsis

Liu

Yang

2022

Front. Immunol.

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Sepsis is recognized as a life-threatening multi-organ dysfunction resulting from a dysregulated host response to infection. Although the incidence and mortality of sepsis decrease significantly due to timely implementation of anti-infective and support therapies, accumulating evidence suggests that a great proportion of survivors suffer from long-term cognitive impairment after hospital discharge, leading to decreased life quality and substantial caregiving burdens for family members. Several mechanisms have been proposed for long-term cognitive impairment after sepsis, which are not mutually exclusive, including blood-brain barrier disruption, neuroinflammation, neurotransmitter dysfunction, and neuronal loss. Targeting these critical processes might be effective in preventing and treating long-term cognitive impairment. However, future in-depth studies are required to facilitate preventive and/or treatment strategies for long-term cognitive impairment after sepsis.

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“…Then, GSDMD-NT becomes a ring-like structure and forms holes in the cell membrane, which causes the production of IL-1β and IL-18, and leads to cell lysis. The canonical signaling pathway plays a potential role in the pathogenesis of SAE, and the inhibition of pyroptosis may be a useful therapeutic target for SAE ( 95 , 96 ).…”

Section: The Immune Response Of Cns In the Development Of Saementioning

confidence: 99%

“…With this regard, expressions of NLRP3, GSDMD-NT, and cleaved caspase-1 were augmented in the brain of septic mice, and the upregulation of NLRP3, caspase-1, and gasdermin-D in the hippocampus resulted in the cognitive deficits in the mice model of SAE by inducing pyroptosis ( 99 ). Recently, we found that sestrin 2 improved the outcome of sepsis by decreasing the NLRP3/caspase-1-dependent pyroptosis, and it was closely related to the protein kinase RNA (PER)-like ER kinase (PERK)-activating transcription factor (ATF)4-C/EBP homologous protein (CHOP) pathway ( 95 ). Moreover, Lei et al ( 100 ) explored the nexus between autophagy and pyroptosis in mice with SAE, and the results showed that both autophagy and pyroptosis were involved in the development of SAE in mice, and pannexin-1 decreased the occurrence of pyroptosis by autophagy.…”

Section: The Immune Response Of Cns In the Development Of Saementioning

confidence: 99%

“…Moreover, Lei et al ( 100 ) explored the nexus between autophagy and pyroptosis in mice with SAE, and the results showed that both autophagy and pyroptosis were involved in the development of SAE in mice, and pannexin-1 decreased the occurrence of pyroptosis by autophagy. Collectively, it was suggested that both the canonical and non-canonical pathways of cell pyroptosis are associated with cell apoptosis induced by LPS ( 95 ). However, the exact functions of the canonical and non-canonical pyroptosis together with the networks among pyroptosis, apoptosis, and autophagy in SAE are required in further studies.…”

Section: The Immune Response Of Cns In the Development Of Saementioning

confidence: 99%

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Neuroimmune Regulation in Sepsis-Associated Encephalopathy: The Interaction Between the Brain and Peripheral Immunity

Liu

et al. 2022

Front. Neurol.

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Sepsis-associated encephalopathy (SAE), the most popular cause of coma in the intensive care unit (ICU), is the diffuse cerebral damage caused by the septic challenge. SAE is closely related to high mortality and extended cognitive impairment in patients in septic shock. At present, many studies have demonstrated that SAE might be mainly associated with blood–brain barrier damage, abnormal neurotransmitter secretion, oxidative stress, and neuroimmune dysfunction. Nevertheless, the precise mechanism which initiates SAE and contributes to the long-term cognitive impairment remains largely unknown. Recently, a growing body of evidence has indicated that there is close crosstalk between SAE and peripheral immunity. The excessive migration of peripheral immune cells to the brain, the activation of glia, and resulting dysfunction of the central immune system are the main causes of septic nerve damage. This study reviews the update on the pathogenesis of septic encephalopathy, focusing on the over-activation of immune cells in the central nervous system (CNS) and the “neurocentral–endocrine–immune” networks in the development of SAE, aiming to further understand the potential mechanism of SAE and provide new targets for diagnosis and management of septic complications.

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Roles of the pyroptosis signaling pathway in a sepsis-associated encephalopathy cell model

Cited by 11 publications

References 35 publications

HSF1 Alleviates Brain Injury by Inhibiting NLRP3-Induced Pyroptosis in a Sepsis Model

HSF1 Alleviates Brain Injury by Inhibiting NLRP3-Induced Pyroptosis in a Sepsis Model

Current Understanding of Long-Term Cognitive Impairment After Sepsis

Neuroimmune Regulation in Sepsis-Associated Encephalopathy: The Interaction Between the Brain and Peripheral Immunity

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