Aernoud Fiolet

261 Colchicine Attenuates Inflammation Beyond the Inflammasome of the NLRP3 inflammasome inhibition, as suggested by a 10.7% reduction of NF- κ B (nuclear factor– κ B) essential modulator (PFDR=0.008), an activator of NF- κ B, which is necessary for NLRP3 inflammasome activation. Eleven proteins showed a large median reduction (>10%) after colchicine (Figure). These proteins are not directly involved in the NLRP3 inflammasome pathway; glycoprotein VI (−15.3%; PFDR<0.001), CD40 ligand (−15.2%; PFDR<0.001), pro–IL-16 (−13.7%; PFDR=0.002), and C-C motif chemokine 17 (−10.0%; PFDR=0.007) play important roles in the adaptive immune system, hemostasis, or both. The strongest attenuation was observed in proteins involving neutrophil degranulation: myeloblastin (−25.7%; PFDR<0.001), carcinoembryonic antigen- related cell adhesion molecule 8 (−25.4%; PFDR<0.001), azurocidin (−20.4%; PFDR<0.001), and myeloperoxidase (−15.2%; PFDR<0.001) showed strong reductions after colchicine, and all are present in the granules of neutrophils. Neutrophils are the main source of circulating urokinase plasminogen activator surface receptor (−10.1%; PFDR<0.001). Colchicine accumulates preferably in neutrophils, interfering with neutrophil adhesion, mobilization, and recruitment, and inhibiting neutrophil chemotaxis and superoxide production. 3 Our results support an important inhibitory effect of colchicine on neutrophils, which have been suggested to contribute to progression of atherogenesis. 4 Twenty-three proteins showed significant median increase after colchicine treatment (PFDR<0.05). The strongest increase was measured in levels of intestinal fatty acid–binding protein (18.5%; PFDR=0.027), a biomarker of intestinal barrier dysfunction, and myoglobin (17.8%; PFDR<0.001), the oxygen-carrying pigment of muscle tissues related to myopathy, which might relate to the occurrence of known (subclinical) gastrointestinal and myopathic side effects of colchicine. 5 Protein-glutamine γ -glutamyltransferase 2 (15.2%; PFDR<0.001) is related to tissue repair, whereas fibroblast growth factor 21 (11.8%; PFDR<0.001) and insulin-like growth factor-binding protein 1 (10.6%; PFDR<0.001) could protect against atherosclerosis (Figure). Treatment with colchicine resulted in a significant reduction of median high- sensitivityC-reactive protein from1.52mg/L (interquartile range, 0.66–3.43mg/L) to 1.00 mg/L (interquartile range, 0.37–2.28 mg/L; PFDR<0.001). In only 6 proteins, change in high-sensitivity C-reactive protein correlated significantly with change in protein level: IL-6 (r=0.461; PFDR<0.001), E-selectin (r=0.273; PFDR=0.008), matrix metalloproteinase-9 (r=0.241; PFDR= 0.028), cathepsin Z (r=0.240; PFDR=0.022), retinoic acid receptor responder protein 2 (r=0.232;