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

Abstract

The critical size for strong interaction of hydrophobic particles with phospholipid bilayers has been predicted to be 10 nm. Because of the wide spreading of nonpolar nanoparticles (NPs) in the environment, we aimed to reveal the ability of living organisms to entrap NPs via formation of neutrophil extracellular traps (NETs). Upon interaction with various cell types and tissues, 10-to 40-nmsized NPs induce fast (<20 min) damage of plasma membranes and instability of the lysosomal compartment, leading to the immediate formation of NETs. In contrast, particles sized 100-1,000 nm behaved rather inertly. Resulting NET formation (NETosis) was accompanied by an inflammatory reaction intrinsically endowed with its own resolution, demonstrated in lungs and air pouches of mice. Persistence of small NPs in joints caused unremitting arthritis and bone remodeling. Small NPs coinjected with antigen exerted adjuvant-like activity. This report demonstrates a cellular mechanism that explains how small NPs activate the NETosis pathway and drive their entrapping and resolution of the initial inflammatory response.nanoparticles | size | neutrophils | NETosis | inflammation

Oxidative Burst-Dependent NETosis Is Implicated in the Resolution of Necrosis-Associated Sterile Inflammation

“…Consistent with previous findings employing epithelial and red blood cells (RBC) (22), we report that nanodiamonds induce cellular damage in human and murine leukocytes in vitro . In contrast, microdiamonds did not affect the membrane integrity of these cells.…”

“…These NETs sequestered and entrapped the nanodiamonds. NETosis induced by particulate matter has already been reported for MSU (30), calcium carbonate (31), calcium oxalate (32), and diamonds (22). The mechanism of crystal-induced NETosis is associated with the necroptosis pathway (33).…”

“…Further reports on neutrophils reacting to tissue damage induced by nanoparticles are scarce. We have recently demonstrated that the size of particles critically determines NETosis, and this is associated with the resolution of an initial neutrophil-driven inflammation in air pouches (22). Microdiamonds of 1 μm were not taken up by granulocytes in vitro , whereas small nanodiamonds induced NETosis due to their size and hydrophobicity.…”

“…We have recently shown that diamond nanoparticles induce membrane damage in a broad spectrum of cells in vitro and in vivo (22). The ability to penetrate through plasma membranes was also demonstrated for C60 fullerenes (23) and for single- and multi-walled carbon nanotubes (24).…”

“…Taking together, metabolically inert nanoparticles induce sterile tissue damage upon injection. Since small nanodiamonds also cause NETosis in neutrophils (22), we hypothesized that such a necrosis-inducing trigger does not only mount sterile inflammation but also a robust resolution response. Thus, we aimed to create an in vivo model of permanent sterile inflammation to reveal the role of oxidative burst-dependent NETosis in the context of tissue damage in the absence of pathogens.…”