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Intrauterine exposure to oxidative stress induces caspase-1-dependent enteric nerve cell pyroptosis

Lingling Zhou1,2, Bingyu Wang1,3, Hua Xie1

  • 1Department of Neonatal Surgery, Children's Hospital of Nanjing Medical University, Nanjing, People's Republic of China.

Pediatric Surgery International
|August 22, 2022
PubMed

Insights

Oxidative stress triggers pyroptosis, a form of cell death, in developing enteric nervous system cells. This process, mediated by NLRP3 inflammasomes and caspase-1, contributes to abnormal development and Hirschsprung disease.

Area of Science:

  • Developmental biology
  • Neuroscience
  • Cellular biology

Background:

  • Hirschsprung disease (HSCR) is a congenital disorder characterized by abnormal enteric nervous system (ENS) development.
  • Oxidative stress is implicated in various developmental abnormalities, but its specific role in ENS development remains unclear.

Purpose of the Study:

  • To investigate whether oxidative stress causes developmental abnormalities of the enteric nervous system during the embryonic period.
  • To elucidate the molecular mechanisms underlying oxidative stress-induced ENS defects.

Main Methods:

  • Established pregnant rat and cellular oxidative stress models.
  • Analyzed pyroptosis markers (NLRP3, ASC, caspase-1) and cathepsin D expression.
  • Utilized reactive oxygen species scavengers, caspase-1 inhibitors, and NLRP3 siRNA to assess protective effects.

Main Results:

  • Overexpression of pyroptosis markers (NLRP3, ASC, caspase-1) was observed in HSCR lesions and in pups exposed to oxidative stress.
  • Cathepsin D expression was significantly decreased in the intestinal tissues of pups in the oxidative stress group.
  • Interventions targeting reactive oxygen species, caspase-1, and NLRP3 reversed markers of cell death and damage.

Conclusions:

  • Oxidative stress induces enteric nerve cell death via caspase-1-dependent pyroptosis, mediated by NLRP3 inflammasomes.
  • This mechanism contributes to abnormal enteric nervous system development and may play a role in Hirschsprung disease.
Abstract

Keywords:
Caspase-1Hirschsprung diseaseNLRP3Oxidative stressPyroptosis

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