Colchicine Alleviates Interstitial Lung Disease in an Experimental Autoimmune Myositis Murine Model by Inhibiting the Formation of Neutrophil Extracellular Traps.

Abstract

Our previous study has shown that neutrophil extracellular traps (NETs) were associated with idiopathic inflammatory myopathy-related interstitial lung disease (IIM-ILD). Colchicine plays an anti-inflammatory role mainly by inhibiting the activity and chemotaxis of neutrophils. This study aims to verify therapeutic effects and mechanism of colchicine in IIM-ILD. 20 experimental autoimmune myositis (EAM) model mice were randomly divided into EAM group, colchicine groups (1, 2 mg/kg) and Cl-amidine group (positive control), five mice in the control group received sham modeling procedure. After 5 weeks, the mice were sacrificed to evaluate the degree of pulmonary interstitial lesions and the formation of NETs. Human neutrophils were pretreated with colchicine (40 nmol/L) and stimulated to form NETs. Human pulmonary microvascular endothelial cells (HPMECs) were pretreated with colchicine and stimulated with NETs, and markers of inflammation and pyroptosis were detected. Pathological staining of lung tissue showed that severity of ILD and NETs infiltration were significantly alleviated in colchicine groups (P < 0.01) and in the Cl-amidine group (P < 0.01), and the serum level of NETs was also significantly decreased in colchicine groups (P < 0.05) and in the Cl-amidine group (P < 0.05). Colchicine intervention significantly attenuated PMA-induced NETs formation in vitro (P < 0.0001). Colchicine intervention significantly reduced marker expressions of inflammasome and pyroptosis in HPMECs stimulated by NETs and in the lung tissue of EAM mice. Colchicine can alleviate ILD in EAM mice by inhibiting NETs formation, inflammasome activation and endothelial cell pyroptosis. These findings provide a basis for targeting NETs and colchicine administration in the treatment of myositis-associated ILD.