Colchicine prevents disease progression in viral myocarditis via modulating the NLRP3 inflammasome in the cardiosplenic axis

Abstract

AimThe acute phase of a coxsackievirus 3 (CVB3)-induced myocarditis involves direct toxic cardiac effects and the systemic activation of the immune system, including the cardiosplenic axis. Consequently, the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome pathway is activated, which plays a role in disease pathogenesis and progression. The anti-inflammatory drug colchicine exerts its effects, in part, via reducing NLRP3 activity, and has been shown to improve several cardiac diseases, including acute coronary syndrome and pericarditis. The aim of the present study was to evaluate the potential of colchicine to improve experimental CVB3-induced myocarditis. Methods and results C57BL6/j mice were intraperitoneally injected with 1 × 10 5 plaque forming units of CVB3. After 24 h, mice were treated with colchicine (5 μmol/kg body weight) or phosphate-buffered saline (PBS) via oral gavage (p.o.). Seven days post infection, cardiac function was haemodynamically characterized via conductance catheter measurements. Blood, the left ventricle (LV) and spleen were harvested for subsequent analyses. In vitro experiments on LV-derived fibroblasts (FB) and HL-1 cells were performed to further evaluate the anti-(fibro)inflammatory and anti-apoptotic effects of colchicine via gene expression analysis, Sirius Red assay, and flow cytometry. CVB3 + colchicine mice displayed improved LV function compared with CVB3 + PBS mice, paralleled by a 4.7-fold (P < 0.01) and 1.7-fold (P < 0.001) reduction in LV CVB3 gene expression and cardiac troponin-I levels in the serum, respectively. Evaluation of components of the NLRP3 inflammasome revealed an increased percentage of apoptosis-associated speck-like protein containing a CARD domain (ASC)-expressing, caspase-1-expressing, and interleukin-1β-expressing cells in the myocardium and in the spleen of CVB3 + PBS vs. control mice, which was reduced in CVB3 + colchicine compared with CVB3 + PBS mice. This was accompanied by 1.4-fold (P < 0.0001), 1.7fold (P < 0.0001), and 1.7-fold (P < 0.0001) lower numbers of cardiac dendritic cells, natural killer cells, and macrophages, respectively, in CVB3 + colchicine compared with CVB3 + PBS mice. A 1.9-fold (P < 0.05) and 4.6-fold (P < 0.001) reduced cardiac gene expression of the fibrotic markers, Col1a1 and lysyl oxidase, respectively, was detected in CVB3 + colchicine mice compared with CVB3 + PBS animals, and reflected by a 2.2-fold (P < 0.05) decreased Collagen I/III protein ratio. Colchicine further reduced Col3a1 mRNA and collagen protein expression in CVB3-infected FB and lowered apoptosis and viral progeny release in CVB3-infected HL-1 cells. In both CVB3 FB and HL-1 cells, colchicine down-regulated the NLRP3 inflammasome-related components ASC, caspase-1, and IL-1β. Conclusions Colchicine improves LV function in CVB3-induced myocarditis, involving a decrease in cardiac and splenic NLRP3 inflammasome activity, without exacerbation of CVB3 load.

Recombinant human angiotensin-converting enzyme 2 plays a protective role in mice with sepsis-induced cardiac dysfunction through multiple signaling pathways dependent on converting angiotensin II to angiotensin 1–7

“…Pyroptosis, a form of inflammation programmed cell death, is involved in either inflammatory or non-inflammatory heart disease ( 65 , 66 ). NLRP3 inflammasome activation plays a significant role in initiating inflammatory response and pyroptosis, contributing to cardiac injury and dysfunction in both ischemic and inflammatory heart disease ( 67 , 68 ).…”

“…Pyroptosis procedure mediated by GSDMD cleavage has a detrimental effect on cardiac function ( 70 ). Inhibitors of NLRP3 inflammasome-related pro-inflammatory factors and depletion of pyroptosis by knocking out NLRP3 or other components of NLRP3 inflammasome (ASC, GSDMD, or caspase-1) attenuate cardiac injury and improve cardiac function ( 67 , 68 , 70 - 72 ). Our observation in the present study also indicated the involvement of NLRP3 inflammasome activation in LPS-induced cardiac dysfunction.…”

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“…A course of doxycycline 200 mg stat and 100 mg twice daily for 10 days was commenced to treat the infective consolidation. Colchicine 500 micrograms once daily and ibuprofen 400 mg three times a day were commenced to treat the myopericarditis [ 7 ]. Her lupus medications, prednisolone 5 mg once daily and hydroxychloroquine alternating between 200 mg and 400 mg once daily, were continued.…”

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“…IL-1ß is generated by the Nod-like receptor protein 3 (NLRP3) inflammasome, a multiprotein complex, part of the innate immunity, which gets activated following dangerous associated molecular patterns, like the alarmins S100A8 and S100A9 ( 18 , 19 ), tobacco ( 20 ) and cholesterol crystals ( 21 ), as well as by pathogen associated molecular patterns (PAMPs), like coxsackievirus B3 ( 22 , 23 ) and human papillomavirus ( 24 ), covering a broad spectrum of triggers present in or provoking both CVD/heart failure and cancer ( 25 ). Oxidized LDL and cholesterol crystals are DAMPs which activate the NLRP3 inflammasome and lead to IL-1ß secretion.…”