NLRP3-directed antisense oligonucleotides reduce microglial immunoactivities in vitro

Area of Science:

• Neuroimmunology
• Molecular Biology
• Pharmacology

Background:

• Alzheimer's disease (AD) is linked to cerebral Amyloid-β (Aβ) deposition.
• Aβ deposition triggers NLRP3 inflammasome activation, releasing pro-inflammatory cytokines like interleukin-1β (IL-1β).
• NLRP3 inflammasome inhibition shows potential in mitigating AD-associated pathology, including microglial dysfunction and memory deficits.

Purpose of the Study:

• To investigate the efficacy of NLRP3-directed antisense oligonucleotides (ASOs) as immune modulators.
• To assess the impact of ASOs on NLRP3 inflammasome activation and IL-1β release in cellular models.

Main Methods:

• Primary murine microglia and human THP-1 cells were treated with NLRP3-directed ASOs.
• Cells were activated using lipopolysaccharide (LPS) with nigericin or Aβ.
• NLRP3 mRNA levels, caspase-1 cleavage, and mature IL-1β release were measured.

Main Results:

• NLRP3 mRNA degradation was confirmed 72 hours post-ASO treatment in murine microglia.
• NLRP3-directed ASOs significantly reduced cleaved caspase-1 and mature IL-1β levels in activated cells.
• Similar suppression of IL-1β release was observed in human THP-1 cells.

Conclusions:

• NLRP3-directed ASOs effectively suppress NLRP3 inflammasome activity and IL-1β release in both murine and human cell lines.
• ASOs represent a potential novel therapeutic strategy for modulating NLRP3 inflammasome activation in neurodegenerative diseases.
• This approach offers an alternative to pharmacological inhibition of the NLRP3 inflammasome complex.