naRNA-LL37 composite DAMPs define sterile NETs as self-propagating drivers of inflammation

Area of Science:

• Immunology
• Molecular Biology
• Dermatology

Background:

• Neutrophil extracellular traps (NETs) are crucial for innate immunity against microbes.
• Dysregulated NET formation is implicated in inflammatory conditions such as atherosclerosis, arthritis, and psoriasis.
• The precise mechanisms linking NETs to inflammation remain incompletely understood.

Purpose of the Study:

• To elucidate the role of NET-associated RNA (naRNA) in amplifying NET formation and driving inflammation.
• To investigate the signaling pathways involved in naRNA-induced neutrophil and keratinocyte activation.
• To explore the therapeutic potential of targeting naRNA sensing in inflammatory diseases.

Main Methods:

• Investigated naRNA's ability to stimulate NET formation in naive polymorphonuclear neutrophils (PMNs).
• Utilized cell-based assays to examine keratinocyte responses to naRNA, including gene expression analysis.
• Employed genetic ablation of RNA sensing in vivo to assess the impact on skin inflammation.
• Characterized the naRNA-LL37 complex as a damage-associated molecular pattern (DAMP).

Main Results:

• naRNA was found to stimulate further NET formation in naive PMNs through a TLR8-NLRP3 inflammasome-dependent pathway.
• Keratinocytes responded to naRNA by upregulating psoriasis-related genes (e.g., IL17, IL36) via atypical NOD2-RIPK signaling.
• In vivo, naRNA induced temporary skin inflammation, which was significantly reduced by inhibiting RNA sensing.
• The naRNA-LL37 DAMP, pre-stored in neutrophil granules, transiently amplifies neutrophil activation.

Conclusions:

• naRNA acts as a potent amplifier of NET formation and associated inflammation.
• The naRNA-LL37 DAMP contributes to sterile inflammation, with potential implications for diseases like psoriasis.
• Targeting naRNA sensing presents a promising therapeutic strategy for managing inflammatory conditions driven by dysregulated NETosis.