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

Objectives The inhibition of pyroptosis has a protective effect in sepsis-associated encephalopathy (SAE). However, the mechanisms underlying pyroptosis in SAE remain to be elucidated. Methods Here, we investigated the effects of the caspase inhibitors, Belnacasan (Beln) and Wedelolactone (Wede), on an induced model of SAE in P12 cells, using immunofluorescence, ELISA, western blotting, and flow cytometry. Results The cell viability decreased, IL-1β and IL-18 secretion increased, and the levels of the caspase cleavage products, N-terminal gasdermin D, cleaved caspase-1, and cleaved caspase-11, increased in P12 cells following combined treatment with lipopolysaccharides (LPS) and adenosine triphosphate (ATP). However, treatment with Beln or Wede ameliorated the effects induced by LPS and ATP. Neither Beln nor Wede notably affected the levels of cell apoptosis-associated proteins but these inhibitors regulated the levels of cell pyroptosis-associated proteins. Further, the combination of Beln and Wede exerted greater inhibitory effects on cell pyroptosis than either Beln or Wede alone. Conclusions The results demonstrated that both the canonical and non-canonical signaling pathways of cell pyroptosis are involved in LPS-induced cell damage and that the non-canonical signaling pathway may be involved to a greater extent. This suggests that the inhibition of pyroptosis may exert potential therapeutic effects on SAE.

[1]  Yan Jiang,et al.  Cannabinoid 1 receptor (CB1R) antagonists play a neuroprotective role in chronic alcoholic hippocampal injury related to pyroptosis pathway. , 2020, Alcoholism, clinical and experimental research.

[2]  J. Lieberman,et al.  FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation , 2020, Nature Immunology.

[3]  Z. Yao,et al.  Silencing lncRNA Lfar1 alleviates the classical activation and pyoptosis of macrophage in hepatic fibrosis , 2020, Cell Death & Disease.

[4]  Liming Yu,et al.  Hypoxia-Induced ROS Contribute to Myoblast Pyroptosis during Obstructive Sleep Apnea via the NF-κB/HIF-1α Signaling Pathway , 2019, Oxidative medicine and cellular longevity.

[5]  Zhanfei Li,et al.  Caspase-1 inhibitor exerts brain-protective effects against sepsis-associated encephalopathy and cognitive impairments in a mouse model of sepsis , 2019, Brain, Behavior, and Immunity.

[6]  Zhaoyu Lin,et al.  Magnesium protects against sepsis by blocking gasdermin D N-terminal-induced pyroptosis , 2019, Cell Death & Differentiation.

[7]  M. Ji,et al.  NLRP3/Caspase-1 Pathway-Induced Pyroptosis Mediated Cognitive Deficits in a Mouse Model of Sepsis-Associated Encephalopathy , 2018, Inflammation.

[8]  J. Gong,et al.  Cathepsin B regulates non‐canonical NLRP3 inflammasome pathway by modulating activation of caspase‐11 in Kupffer cells , 2018, Cell proliferation.

[9]  T. Kang,et al.  Artemisia Extract Suppresses NLRP3 and AIM2 Inflammasome Activation by Inhibition of ASC Phosphorylation , 2018, Mediators of inflammation.

[10]  Zhanfei Li,et al.  Caspase-1-dependent pyroptosis of peripheral blood mononuclear cells predicts the development of sepsis in severe trauma patients , 2018, Medicine.

[11]  E. Miao,et al.  Gasdermins: Effectors of Pyroptosis. , 2017, Trends in cell biology.

[12]  R. Wadgaonkar,et al.  Sepsis-Associated Encephalopathy: The Blood–Brain Barrier and the Sphingolipid Rheostat , 2017, Front. Immunol..

[13]  Dacheng Wang,et al.  Erratum: Pore-forming activity and structural autoinhibition of the gasdermin family , 2016, Nature.

[14]  J. Lieberman,et al.  Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores , 2016, Nature.

[15]  V. Dixit,et al.  GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes , 2016, Proceedings of the National Academy of Sciences.

[16]  V. Dixit,et al.  Inflammasomes: mechanism of assembly, regulation and signalling , 2016, Nature Reviews Immunology.

[17]  Chuan-Qi Zhong,et al.  Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion , 2015, Cell Research.

[18]  P. Brož,et al.  Caspase‐11 activates a canonical NLRP3 inflammasome by promoting K+ efflux , 2015, European journal of immunology.

[19]  Jonathan L. Schmid-Burgk,et al.  Caspase‐4 mediates non‐canonical activation of the NLRP3 inflammasome in human myeloid cells , 2015, European journal of immunology.

[20]  S. Kummerfeld,et al.  Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling , 2015, Nature.

[21]  K. Hua,et al.  Resveratrol inhibits NLRP3 inflammasome activation by preserving mitochondrial integrity and augmenting autophagy , 2015, Journal of cellular physiology.

[22]  Jie Fan,et al.  Programmed cell death and its role in inflammation , 2015, Military Medical Research.

[23]  E. Miao,et al.  Pyroptotic cell death defends against intracellular pathogens , 2015, Immunological reviews.

[24]  W. A. Banks The blood-brain barrier in neuroimmunology: Tales of separation and assimilation , 2015, Brain, Behavior, and Immunity.

[25]  D. Monack,et al.  Revisiting caspase-11 function in host defense. , 2013, Cell host & microbe.

[26]  G. Núñez,et al.  K⁺ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. , 2013, Immunity.

[27]  K. Fitzgerald,et al.  Regulation of inflammasome signaling , 2012, Nature Immunology.

[28]  Richard A. Flavell,et al.  Inflammasomes in health and disease , 2012, Nature.

[29]  Jinfeng Liu,et al.  Non-canonical inflammasome activation targets caspase-11 , 2011, Nature.

[30]  C. Zauner,et al.  Impaired subcortical and cortical sensory evoked potential pathways in septic patients* , 2002, Critical care medicine.

[31]  G. Clermont,et al.  Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care , 2001, Critical care medicine.

[32]  B. Cookson,et al.  Pro-inflammatory programmed cell death. , 2001, Trends in microbiology.

[33]  M. Moskowitz,et al.  Dual Role of Caspase-11 in Mediating Activation of Caspase-1 and Caspase-3 under Pathological Conditions , 2000, The Journal of cell biology.

[34]  Y. Archibald,et al.  The Electroencephalogram in Sepsis‐Associated Encephalopathy , 1992, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[35]  M. A. M. Gakidis,et al.  Wedelolactone suppresses LPS-induced caspase-11 expression by directly inhibiting the IKK Complex , 2004, Cell Death and Differentiation.