Neutrophil Extracellular Traps and Microcrystals

Balázs Rada, Balázs Rada

Abstract

Neutrophil extracellular traps represent a fascinating mechanism by which PMNs entrap extracellular microbes. The primary purpose of this innate immune mechanism is thought to localize the infection at an early stage. Interestingly, the ability of different microcrystals to induce NET formation has been recently described. Microcrystals are insoluble crystals with a size of 1-100 micrometers that have different composition and shape. Microcrystals have it in common that they irritate phagocytes including PMNs and typically trigger an inflammatory response. This review is the first to summarize observations with regard to PMN activation and NET release induced by microcrystals. Gout-causing monosodium urate crystals, pseudogout-causing calcium pyrophosphate dehydrate crystals, cholesterol crystals associated with atherosclerosis, silicosis-causing silica crystals, and adjuvant alum crystals are discussed.

Conflict of interest statement

The author has no conflict of interests to report.

Figures

Figure 1
Figure 1
Neutrophil extracellular traps. (a) This fluorescent image depicts NETs released from human PMNs following CPPD crystal stimulation (50 μg/mL, 3 hrs, unpublished data). PMN DNA was stained by DAPI and the color was artificially turned into white for better visibility. (b) Scheme demonstrating different types of microcrystals that were documented to release DNA from PMNs.
Figure 2
Figure 2
The proposed role of PMNs in the immunopathogenesis of gout. Phase (1) shows the deposition of needle-shaped MSU crystals. Phase (2) depicts PMNs phagocytosing crystals and releasing chemoattractants and NETs. Phase (3) shows the formation of aggregated NETs (aggNET) that provide the structural basis of gouty tophi and contain high concentration of PMN proteases degrading PMN chemoattractants.
Figure 3
Figure 3
PMNs release extracellular DNA in response to Alhydrogel in vitro. Human PMNs seeded on a 96-well black microplate were incubated for 30 minutes in the presence or absence of 10 μM DPI prior stimulation with increasing doses of commercially available Alhydrogel (InvivoGen, cat#: vac-alu-50) or 100 nM PMA. Increase in fluorescence due to extracellular DNA (ecDNA) release was measured in presence of 10 μM Sytox Orange DNA-binding dye for 5 hours with a microplate fluorimeter. DNA release is presented as either relative fluorescence units (RFU) or percentage of maximal DNA released achieved by saponin treatment [4, 20]. (a) Summary of three independent experiments using PMNs obtained from independent human donors. Mean +/− SEM. (b) Representative kinetics of fluorescence results (n = 3). Ut, untreated; PMA, phorbol myristate acetate.

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