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IFN-α and IFN-β inhibit NLRP1-driven PANoptosis

Bhesh Raj Sharma1, Harisankeerth Mummareddy1, Sangappa B Chadchan1

  • 1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

EMBO Reports
|July 29, 2026
PubMed

Insights

Toll-like receptor 4 (TLR4) signaling inhibits NLRP1-mediated PANoptosis, a form of inflammatory cell death. This pathway involves TRIF and IRF3, leading to type I interferons that suppress NLRP1 expression.

Area of Science:

  • Immunology
  • Cellular Biology
  • Molecular Medicine

Background:

  • Innate immune sensors like NLRP1 detect cellular stress and pathogens, initiating inflammatory signaling and cell death.
  • Mutations in NLRP1 are linked to inflammatory diseases, yet its regulatory mechanisms remain unclear.

Purpose of the Study:

  • To investigate the regulation of NLRP1-mediated inflammatory cell death (PANoptosis).
  • To identify signaling pathways that modulate NLRP1 activity in response to innate immune activators.

Main Methods:

  • Utilized lipopolysaccharide (LPS) as a Toll-like receptor 4 (TLR4) ligand to activate innate immunity.
  • Assessed caspase activation, IL-18 release, and PANoptosis in response to LPS and interferons (IFNs).
  • Investigated the roles of TRIF, MyD88, and IRF3 in the signaling pathway.
  • Quantified NLRP1 expression in response to LPS and type I IFNs in murine and human immune cells.

Main Results:

  • LPS inhibits NLRP1-mediated PANoptosis, caspase activation, and IL-18 release.
  • This inhibition is dependent on TRIF and IRF3, indicating a role for TRIF-dependent TLR4 signaling and type I IFN signaling.
  • Type I IFNs (IFN-α, IFN-β) directly inhibit NLRP1-dependent PANoptosis in macrophages and monocytes.
  • LPS and type I IFNs significantly reduce NLRP1 and Nlrp1b expression at the transcriptional level.

Conclusions:

  • A TLR4-TRIF-IRF3 signaling axis induces type I IFNs, which suppress NLRP1 transcription.
  • This negative feedback loop blocks NLRP1-driven PANoptosis, involving caspase-1, caspase-8, and RIPK3.
  • Type I IFNs represent a potential therapeutic target for managing NLRP1-associated inflammatory diseases.

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