Nanoparticles size-dependently initiate self-limiting NETosis-driven inflammation

Area of Science:

• Nanotechnology
• Immunology
• Toxicology

Background:

• Hydrophobic nanoparticles (NPs) interact strongly with cell membranes, with a critical size predicted around 10 nm.
• Nonpolar nanoparticles (NPs) are increasingly prevalent in the environment, necessitating an understanding of biological interactions.
• Neutrophil extracellular traps (NETs) are a key component of the innate immune response.

Purpose of the Study:

• To investigate the ability of living organisms to entrap nonpolar nanoparticles (NPs) through the formation of neutrophil extracellular traps (NETs).
• To elucidate the cellular mechanisms by which small NPs induce NET formation and influence inflammatory responses.
• To assess the long-term effects of NP persistence in tissues and their adjuvant-like properties.

Main Methods:

• Exposure of various cell types and tissues to NPs of different sizes (10-1,000 nm).
• Monitoring of plasma membrane integrity and lysosomal compartment stability.
• Induction and observation of NET formation (NETosis) in vivo (mice lungs and air pouches).
• Assessment of NP persistence in joints and associated pathological changes.
• Evaluation of adjuvant-like activity of small NPs when coinjected with antigen.

Main Results:

• 10- to 40-nm NPs rapidly (<20 min) induced plasma membrane damage and lysosomal instability, leading to NET formation.
• Larger NPs (100-1,000 nm) exhibited inert behavior with minimal interaction.
• NETosis was accompanied by an intrinsic inflammatory response and its resolution in mouse models.
• Persistent small NPs in joints led to chronic arthritis and bone remodeling.
• Small NPs demonstrated adjuvant-like activity when administered with antigens.

Conclusions:

• Small, nonpolar nanoparticles activate a cellular defense pathway (NETosis) leading to their entrapment.
• This mechanism explains the resolution of initial inflammatory responses triggered by small NPs.
• NP size is a critical determinant of biological interaction, inflammatory potential, and long-term tissue effects.
• Understanding NP-induced NETosis is crucial for assessing environmental risks and developing therapeutic strategies.