Colchicine to decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation

Abstract

Obesity is a major risk-factor for the development of insulin resistance, type 2 diabetes, and cardiovascular disease. Circulating molecules associated with obesity, such as saturated fatty acids and cholesterol crystals, stimulate the innate immune system to incite a chronic inflammatory state. Studies in mouse models suggest that suppressing the obesity-induced chronic inflammatory state may prevent or reverse obesity-associated metabolic dysregulation. Human studies, however, have been far less positive, possibly because targeted interventions were too far downstream of the inciting inflammatory events. Recently, it has been shown that, within adipose tissue macrophages, assembly of a multi-protein member of the innate immune system, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, is essential for the induction of this inflammatory state. Microtubules enable the necessary spatial arrangement of the components of the NLRP3 inflammasome in the cell, leading to its activation and propagation of the inflammatory cascade. Colchicine, a medication classically used for gout, mediates its anti-inflammatory effect by inhibiting tubulin polymerization, and has been shown to attenuate macrophage NLRP3 inflammasome arrangement and activation in vitro and in vivo. Given these findings, we hypothesize that, in at-risk individuals (those with obesity-induced inflammation and metabolic dysregulation), long-term colchicine use will lead to suppression of inflammation and thus cause improvements in insulin sensitivity and other obesity-related metabolic impairments.

Effects of colchicine in adults with metabolic syndrome: A pilot randomized controlled trial

“…As obesity‐induced inflammation involves multiple complimentary and redundant inflammatory pathways, blocking a single cytokine (eg, IL‐1β or TNF‐α) may not be sufficient to induce clinically significant metabolic improvements. However, colchicine affects multiple proinflammatory cell types, cytokines, and pathways activated in obesity . Although we hypothesize that colchicine can improve metabolic dysregulation by its ability to impair NLRP3 inflammasome activation, its ability to block neutrophil diapedesis, promote M2 macrophage differentiation, reduce chemotactic and adhesion molecule production, and suppress superoxide production, potentially all contribute to its anti‐inflammatory and potentially prometabolic effects …”

“…One mechanism by which colchicine exerts its anti‐inflammatory effects is by inhibiting NLRP3 inflammasome formation and activation . A recent retrospective study suggested that among patients with gout, long‐term colchicine treatment may have glycaemic benefit; however, to date no randomized controlled trial (RCT) has investigated colchicine's long‐term effects on glucose metabolism in adults with obesity and metabolic syndrome (MetS) . We hypothesized that administration of colchicine to adults with MetS, but who had not yet developed type 2 diabetes, would improve their obesity‐associated metabolic and inflammatory dysregulation.…”

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

“…Colchicine, which is historically used in the treatment of gout, has been shown to induce an anti‐inflammatory response through destabilization of MTs, which subsequently interferes with the assembly of the NOD‐like receptor pyrin domain containing 3 (NLRP3) inflammasome . Activation of the NLRP3 inflammasome within macrophages is commonly implicated in innate immune inflammatory response .…”

“…Colchicine, which is historically used in the treatment of gout, has been shown to induce an anti‐inflammatory response through destabilization of MTs, which subsequently interferes with the assembly of the NOD‐like receptor pyrin domain containing 3 (NLRP3) inflammasome . Activation of the NLRP3 inflammasome within macrophages is commonly implicated in innate immune inflammatory response . NLRP3 uses a mitochondrially bound adapter protein (apoptosis‐associated speck‐like protein) containing a caspase recruitment domain to recruit caspase‐1 to the complex, followed by autocatalytic processing and activation, ultimately facilitating the cleavage of proinflammatory cytokines IL‐1β and IL‐18 to their activated forms .…”

Anti-Inflammatory Therapy for Atherosclerosis: Contribution to and Lessons of Rheumatology

“…Один из основных механизмов действия колхицина связан с подавлением синтеза ИЛ1β за счет интерференции с ак-тивацией NALP3-инфламмасомы [43]. По данным иссле-дования LoDoCo (Low-Dose Colchicine trial), у пациентов со стабильной ИБС прием колхицина (0,5 мг/сут) в сочета-нии со стандартной терапией приводит к снижению часто-ты кардиоваскулярных катастроф [44].…”