Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity

Yiwei Feng1,2,3, Lishan Lin1,2, Tengteng Wu1,2,4

  • 1Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.

Cell Death & Disease
|January 12, 2024
PubMed

Insights

Microinfarcts worsen recurrent stroke by causing trained immunity in microglia. Targeting NLRP3 in microglia may prevent this harmful immune memory and reduce stroke recurrence.

Area of Science:

  • Neuroscience
  • Immunology
  • Stroke Research

Background:

  • Microinfarcts are prevalent in the elderly and increase stroke vulnerability.
  • The precise impact of microinfarcts on recurrent stroke remains unclear.

Purpose of the Study:

  • To investigate the detrimental effects of microinfarcts on recurrent stroke.
  • To elucidate the underlying mechanisms of microinfarct-induced exacerbation of stroke.

Main Methods:

  • Induction of microinfarcts using two-photon laser and secondary photothrombotic stroke.
  • Analysis of microglial activation, inflammatory responses, and molecular pathways.
  • Utilizing NLRP3 knockout in microglia for mechanistic studies.

Main Results:

  • Microinfarcts induced trained immunity in microglia, enhancing pro-inflammatory responses and ischemic injury in secondary strokes.
  • NLRP3 in microglia was identified to interact with the MLL1 complex, increasing H3K4 methylation and mediating innate immune memory.
  • NLRP3 knockout in microglia attenuated trained immunity and mitigated the adverse effects of microinfarcts on recurrent stroke.

Conclusions:

  • Trained immunity plays a significant role in the detrimental effects of microinfarcts on recurrent stroke.
  • NLRP3 is crucial for the formation of microinfarct-induced innate immune memory.
  • Targeting NLRP3 in microglia presents a potential therapeutic strategy for recurrent stroke prevention.

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