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. 2012 Dec 10:3:376.
doi: 10.3389/fimmu.2012.00376. eCollection 2012.

Bonding the foe - NETting neutrophils immobilize the pro-inflammatory monosodium urate crystals

Christine Schorn  1 , Christina Janko, Veit Krenn, Yi Zhao, Luis E Munoz, Georg Schett, Martin Herrmann
Affiliations

Bonding the foe - NETting neutrophils immobilize the pro-inflammatory monosodium urate crystals (V体育安卓版)

Christine Schorn et al. Front Immunol. .

Abstract

In the presence of sodium, uric acid from purine metabolism precipitates as monosodium urate (MSU) needles and forms renal calculi or causes gouty arthritis in kidneys and joints, respectively. The latter is characterized by red, hot, and swollen arthritic joints. Here we report the in vitro effect of MSU crystals on blood granulocytes and analyze their contribution to granuloma formation and neutrophil extracellular traps (NETs) formation (NETosis) in synovial fluid of patients with gouty arthritis in vivo. We observed that MSU crystals induce NETosis in vitro in a reactive oxygen species (ROS)-dependent manner VSports手机版. Indeed, blocking ROS (e. g. , the oxidative burst) by various anti-oxidants partially inhibited NETosis induced by MSU crystals. Analyses of synovial fluids and of tissue sections of patients suffering from gout revealed that NETs are also formed in vivo, especially during acute gouty flares and/or granuloma formation. Since prolonged exposure to NETs carries the risk for the development of chronic inflammation we also studied the opsonization of NETs, as a prerequisite for their clearance. The established dead cells' opsonins C3b, galectin-9, and CRP decorated the residual dead cells' corpses and opsonized these for disposal. Surprisingly, all three soluble pattern recognizing molecules spared the spread NET structures. We conclude that (i) MSU crystals are strong inducers of ROS-dependent NETosis and (ii) that the prolonged presence of NET-pathogen or NET-crystal aggregates observed in patients with systemic autoimmunity, especially in those with low serum DNase-1 activity, cannot be compensated by CRP, complement, and galectin-mediated phagocytic clearance. .

Keywords: MSU; NETosis; NETs; ROS; gout; inflammation; opsonins. V体育安卓版.

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Figures

FIGURE 1
FIGURE 1
MSU-induced NET formation depends on oxidative stress (ROS). (A) Whole blood was treated with or without MSU (n = 3 per group) and analyzed for ROS production by cytofluorometry. MSU crystals induce oxidative stress (ROS) in neutrophils. **P < 0.01. (B–E) Whole blood was incubated with MSU in the absence (B) or the presence of BHT (C), BHA (D), or ascorbic acid (E). Cytospins were stained for extranuclear DNA. NET formation by neutrophils after incubation with MSU was inhibited by the anti-oxidants BHT (C), BHA (D), and ascorbic acid (E). All experiments were performed at least three times. Scale bars, 100 μm.
FIGURE 2
FIGURE 2
Patients with MSU-induced inflammation display extranuclear DNA in tissue sections. Revealed by DNA staining with propidium iodide, sections of gouty granulomas (A) display extranuclear DNA (arrows). Synovial fluids of patients suffering from gouty arthritis display extranuclear DNA (arrows) visualized by staining with DAPI (B,C). All MSU crystals (artificially colored in yellow in C) were associated with NET structures (C). Sections of human synovial control (D) and cytospins of synovial fluids from MSU-negative arthritis (E) exclusively showed nuclear DNA distribution. All experiments were performed at least five times. Scale bars, 100 μm.
FIGURE 3
FIGURE 3
The dead cells’ ligands C3b, CRP, and galectin-9 do not opsonize NETs. (A–D) Isolated PMN were incubated with MSU for 5 h at 37°C and then fixed with 1% PFA. Cytospins were prepared and NETs visualized by PI staining (red). Anti-C3b (A), CRP (B), and galectin-9 (C) bind to PMN corpses but not to NETs (arrows). Antibodies against dsDNA as positive control (D) bind cell remnants and NETs (arrows). Scale bars, 50 μm.
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