NAD+ depletion links metabolic stress to drive innate immune priming and selectively control PANoptosis

Area of Science:

• Immunology
• Cellular Metabolism
• Molecular Biology

Background:

• The innate immune system initiates responses to infection and damage, but aberrant inflammatory cell death can be pathogenic.
• Cellular metabolic disruption is linked to inflammatory cell death, yet mechanistic links remain unclear.
• Understanding these connections is crucial for identifying therapeutic targets.

Purpose of the Study:

• To investigate the role of nicotinamide adenine dinucleotide (NAD+) in programmed cell death pathways.
• To determine if NAD+ levels influence pyroptosis, necroptosis, PANoptosis, and ferroptosis.
• To elucidate the mechanisms by which NAD+ affects cell death, particularly PANoptosis.

Main Methods:

• Assessed intracellular NAD+ levels in response to various cell death triggers.
• Manipulated NAD+ levels to observe effects on pyroptosis, necroptosis, PANoptosis, and ferroptosis.
• Analyzed the expression of key regulators, such as IRF1, following NAD+ restoration.

Main Results:

• Intracellular NAD+ was depleted across multiple cell death pathways, including pyroptosis, necroptosis, PANoptosis, and ferroptosis.
• Restoring NAD+ levels specifically inhibited PANoptosis, but not other forms of cell death.
• Mechanistically, NAD+ restoration suppressed the expression of PANoptosis regulators like IRF1, indicating suppression of immune sensor priming.

Conclusions:

• NAD+ depletion serves as an early signaling event in cell death.
• Restoring NAD+ selectively blocks PANoptosis by inhibiting its priming phase.
• Targeting NAD+ metabolism presents a potential therapeutic strategy for inflammatory and infectious diseases involving dysregulated PANoptosis.