Biochimica et biophysica acta. Molecular basis of disease · 2024
Colchicine inhibits monosodium urate crystal-mediated inflammation by influencing F-actin formation.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Zhu Lingjiang, Wang Yuqi, Shan Lizhen, Xue Yu, Schett Georg, Herrmann Martin, Liu Lei
Аннотация
OBJECTIVES: To understand the mechanism by which colchicine inhibits the inflammatory properties of monosodium urate (MSU) crystal deposits and tophi.
METHODS: We investigated the effects of colchicine on the inflammatory properties of monosodium urate (MSU) crystal deposits in several models: (i) In vitro tophus formation by MSU and neutrophils; (ii) MSU-induced peritonitis model; (iii) Alpha-1-antitrypsin-induced peritoneal MSU flare model; (iv) MSU-induced arthritis model. We measured neutrophil numbers, NET formation, IL-1β production and F-actin generation by MSU crystals. In addition, we tested the effect of actin inhibitors SMIFH2, Cytochalasin B and Latrunculin B in the models.
RESULTS: Colchicine did not affect neutrophil numbers in all these models. However, colchicine was highly effective to inhibit NET formation, IL-1β production and F-actin generation indicating less pronounced tophus formation, lower inflammatory properties of tophi and reduced conversion from G-actin into F-actin, respectively. F-actin was shown to accumulate in tophi without presence of colchicine and being resistant to degradation by DNase I. Actin inhibitors SMIFH2 and Cytochalasin B significantly reduced IL-1β and neutrophil elastase levels and mitigated MSU-induced arthritis.
CONCLUSION: Colchicine effects on gout flares are not based on reducing neutrophil numbers but on changing the functional properties of tophi by reducing their DNase-resistant F-actin concentrations and thereby reducing the negative impact of NETs on IL-1β production and the pro-inflammatory state of tophi. Actin inhibitors may be interesting tools to convey anti-inflammatory properties and reduction of flares in gout patients.
METHODS: We investigated the effects of colchicine on the inflammatory properties of monosodium urate (MSU) crystal deposits in several models: (i) In vitro tophus formation by MSU and neutrophils; (ii) MSU-induced peritonitis model; (iii) Alpha-1-antitrypsin-induced peritoneal MSU flare model; (iv) MSU-induced arthritis model. We measured neutrophil numbers, NET formation, IL-1β production and F-actin generation by MSU crystals. In addition, we tested the effect of actin inhibitors SMIFH2, Cytochalasin B and Latrunculin B in the models.
RESULTS: Colchicine did not affect neutrophil numbers in all these models. However, colchicine was highly effective to inhibit NET formation, IL-1β production and F-actin generation indicating less pronounced tophus formation, lower inflammatory properties of tophi and reduced conversion from G-actin into F-actin, respectively. F-actin was shown to accumulate in tophi without presence of colchicine and being resistant to degradation by DNase I. Actin inhibitors SMIFH2 and Cytochalasin B significantly reduced IL-1β and neutrophil elastase levels and mitigated MSU-induced arthritis.
CONCLUSION: Colchicine effects on gout flares are not based on reducing neutrophil numbers but on changing the functional properties of tophi by reducing their DNase-resistant F-actin concentrations and thereby reducing the negative impact of NETs on IL-1β production and the pro-inflammatory state of tophi. Actin inhibitors may be interesting tools to convey anti-inflammatory properties and reduction of flares in gout patients.