NLRP3/Caspase-1 Pathway-Induced Pyroptosis Mediated Cognitive Deficits in a Mouse Model of Sepsis-Associated Encephalopathy

Abstract

Sepsis-associated encephalopathy (SAE) is a common complication that leads to long-term cognitive impairments and increased mortality in sepsis survivors. The mechanisms underlying this complication remain unclear and an effective intervention is lacking. Accumulating evidence suggests the nucleotide-binding domain-like receptor protein3 (NLRP3)/caspase-1 pathway is involved in several neurodegenerative diseases. Thus, we hypothesized that the NLRP3/caspase-1 pathway is involved in NLRP3-mediated pyroptosis, maturation and release of inflammatory cytokines, and cognitive deficits in SAE. We used the NLRP3 inhibitor MCC950 and the caspase-1 inhibitor Ac-YVAD-CMK to study the role of the NLRP3/caspase-1 pathway in pyroptosis and cognitive deficits in a mouse model of SAE. Mice were randomly assigned to one of six groups: sham+saline, sham+MCC950, sham+Ac-YVAD-CMK, cecal ligation and puncture (CLP)+saline, CLP+MCC950, and CLP+Ac-YVAD-CMK. Surviving mice underwent behavioral tests or had hippocampal tissues collected for histochemical analysis and biochemical assays. Our results show that CLP-induced hippocampus-dependent memory deficits are accompanied by increased NLRP3 and caspase-1 positive cells, and augmented protein levels of NLRP3, caspase-1, gasdermin-D, and pro-inflammatory cytokines in the hippocampus. In addition, administration of MCC950 or Ac-YVAD-CMK rescues cognitive deficits and ameliorates increased hippocampal NLRP3-mediated neuronal pyroptosis and pro-inflammatory cytokines. Our results suggest that the NLRP3/caspase-1 pathway-induced pyroptosis mediates cognitive deficits in a mouse model of SAE.

X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

“…The activation of the NLRP3 inflammasome also plays a role in the pathophysiology of sepsis and septic cardiomyopathy ( 57 ). Pharmacological inhibition of NLRP3 activation with MCC950 (NLRP3 inflammasome inhibitor) reduced the neurological and cognitive impairment in septic animals ( 58 ). It has also been reported that genetic deficiency of NLRP3 promotes resolution of inflammation in polymicrobial sepsis ( 59 ).…”

Inflammasome and Cognitive Symptoms in Human Diseases: Biological Evidence from Experimental Research

“…However, these symptoms are reduced by a caspase-1 specific inhibitor, which suppresses NLRP3 inflammasome activity [15]. Mice subjected to CLP exhibit hippocampal memory impairment in a fear conditioning test, damaged hippocampal structure, activation of the NLRP3/caspase-1 pathway, increased pyroptosis, and inflammatory cytokines such as IL-1β and IL-18; however, NLRP3 inhibition reversed these outcomes after CLP injury [62], suggesting the involvement of NLRP inflammasome in SAE-associated cognitive disorders.…”

“…In SAE models, resveratrol, Ac-Tyr-Val-Ala-Asp-chloromethylketone (Ac-YVAD-CMK), and MCC950 show protective effects against inflammasome and cognitive dysfunction [15,61,62]. Resveratrol is a natural phenol known as a potential therapeutic agent in neurodegenerative diseases.…”

“…Ac-YVAD-CMK, a caspase-1 inhibitor, can reduce the expressions of NLRP3 inflammasome, IL-1β, and IL-18 in the hippocampus and attenuate memory deficits and emotional abnormalities [15]. MCC950, an NLRP3 inhibitor, or Ac-YVAD-CMK ameliorates neuronal pyroptosis and neuroinflammation in the hippocampus, thereby decreasing cognitive impairment [62].…”

Betulinic Acid Inhibits ROS-Mediated Pyroptosis in Spinal Cord Injury by Augmenting Autophagy via the AMPK-mTOR-TFEB Signaling Pathway

“…Pyroptosis, an in ammatory form of programmed cell death, is known to play a detrimental role in acute central nervous system (CNS) injuries such as traumatic brain injury, cerebral ischemia, and SCI [13][14][15]. Morphologically, pyroptosis is characterized by cell swelling, rupture, and release of cytoplasmic contents [16]. Mechanistically, following CNS injury, in ammasomes (such as NLRP3, ASC, Caspase-1) are activated to cleave GSDMD and release proin ammatory cytokines (interleukin-1β and 18), ultimately leading to pyroptosis [16][17][18].…”