Colchicine as a Potential Anti-Inflammatory Strategy for Aortic Aneurysm
論文ID: CJ-25-0703
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論文ID: CJ-25-0703
Inflammation has long been regarded as a promising therapeutic target for cardiovascular disease (CVD). However, it takes years of research to establish a proof of concept for an inflammation-targeted therapy. CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) marked the first proof-of-concept that inflammation could be a therapeutic target in CVD.1 Nevertheless, canakinumab is not currently regarded as a cost-effective strategy for preventing CVD. Colchicine, an ancient drug known for its anti-inflammatory properties, has emerged as a promising agent for the prevention of CVD,2 and recent clinical trials, COLCOT (Colchicine Cardiovascular Outcome Trial) and LoDoCo2 (Low-Dose Colchicine 2), reported that low-dose colchicine (0.5 mg/day) effectively reduced cardiovascular events in patients who had recently experienced a myocardial infarction or patients with chronic coronary disease, respectively.3,4 In addition to its clinical benefits, colchicine is considered a viable option because of its cost-effectiveness and safety in low-dose usage. Based on these findings, low-dose colchicine was approved in 2023 by the U.S. Food and Drug Administration (FDA) for the reduction of cardiovascular risk.
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Colchicine exerts multiple anti-inflammatory effects mainly by inhibiting microtubule polymerization. In particular, colchicine is concentrated in neutrophils and impairs their function by disrupting microtubules.2 Neutrophils are the primary target of colchicine, which inhibits key functions, including cytokine and chemokine secretion, chemotaxis, and adhesion. Furthermore, colchicine prevents activation of the NLRP3 inflammasome, a complex regulating the release of inflammatory cytokines, interleukin (IL)-1β and IL-18, by activation of caspase-1 (Figure).5 The NLRP3 inflammasome is molecular machinery that senses danger signals and functions as an initiator of inflammation in CVD, including atherosclerosis, aortic aneurysm (AA), aortic dissection, and myocardial infarction.6,7 Recent studies have shown that the NLRP3 inflammasome promotes neutrophil infiltration, contributing to the development of vascular diseases such as atherosclerosis and abdominal AA.8,9 Infiltrated neutrophils promote the formation of neutrophil extracellular traps (NETs), web-like structures composed of decondensed chromatin and neutrophil-derived nuclear, cytosolic or granular proteins. Although NETs primarily defend against pathogens, they can also trigger and amplify inflammasome-mediated inflammatory responses in the progression of vascular diseases.10 Double-strand DNA in NETs induces IL-1β expression and acts as a priming signal for NLRP3 inflammasome activation in macrophages, while also activating the AIM2 inflammasome, a sensor of cytosolic dsDNA.11 Thus, the inflammasome and neutrophils together amplify the inflammatory feedback loop in vascular diseases.
Anti-inflammatory effects of colchicine on the NLRP3 inflammasome and neutrophil-triggered inflammation in aortic aneurysm. Colchicine prevents neutrophil infiltration and NE production during aneurysm progression. Colchicine presumably inhibits NLRP3 inflammasome, either directly or indirectly, by inhibiting NET-mediated priming signals. IL, interleukin; NE, neutrophil elastase; NET, neutrophil extracellular trap.
In this issue of the Journal, Okawa et al. report that oral colchicine administration prevented the progression of angiotensin-II-induced AA in apolipoprotein (Apo) E-deficient mice.12 Colchicine also prevented the collapse of elastic fibers in the aortic wall. Whereas matrix metalloproteinase (MMP)2 and MMP9 activities were unaffected, the number of neutrophil elastase (NE)-positive cells was decreased by colchicine treatment, suggesting blunted matrix degradation by neutrophils. Although the number of CD68-positive macrophages remained unchanged, colchicine decreased the number of NLRP3-positive cells in the aortic wall. Consistently, colchicine significantly reduced the protein levels of NLRP3 and IL-1β induced by priming signals. In vitro experiments showed that colchicine reduced the number of active caspase-1-positive cells in both murine J774A.1 macrophages and primary murine macrophages, indicating that colchicine could directly inhibit inflammasome activation.
A previous study by Usui et al. demonstrated that deficiency of the NLRP3 inflammasome prevented the development of AA in ApoE-deficient mice, suggesting that the NLRP3 inflammasome is a potential therapeutic target.13 This deficiency also reduced macrophage infiltration and MMP activity within the aortic wall. Because Okawa et al. showed that colchicine did not affect MMP2 and MMP9 expression, the inhibitory effect of colchicine on AA likely involves mechanisms other than NLRP3 inflammasome-mediated MMP regulation. Instead, colchicine inhibited the expression of NE, another critical regulator of extracellular matrix degradation. Indeed, Hada et al. recently reported that the pharmacological inhibition of NE suppressed angiotensin II-induced AA in ApoE-deficient mice.14 On the other hand, Chrysanthopoulou et al. recently reported that NET formation contributes to AA development, with NETotic neutrophils detected in AA specimens from patients with essential hypertension.15 In addition, angiotensin II has been shown to induce NETosis in peptidylarginine deiminase type 4 (PAD4)-dependent mechanisms.15 Although NETosis was not evaluated in the study by Okawa et al.,12 its inhibition by colchicine was presumably involved in reducing both NLRP3 inflammasome priming and AA development.
In summary, these findings indicate that colchicine effectively disrupts the inflammatory vicious cycle driven by the NLRP3 inflammasome and infiltrating neutrophils in AA development. Although the COLCOT and LoDoCo2 trials demonstrated the protective effects of low-dose colchicine against cardiovascular events, its efficacy for abdominal AA remains unproven in humans. Further studies are essential to determine its clinical utility in the treatment of AA.
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The authors declare that there are no conflicts of interest.
