Host‐directed anti‐mycobacterial activity of colchicine, an anti‐gout drug, via strengthened host innate resistance reinforced by the IL‐1β/PGE₂ axis

Abstract

Background and Purpose: To diversify and expand possible tuberculosis (TB) drug candidates and maximize limited global resources, we investigated the effect of colchicine, an FDA-approved anti-gout drug, against Mycobacterium tuberculosis (Mtb) infection because of its immune-modulating effects.Experimental Approach: We evaluated the intracellular anti-Mtb activity of different concentrations of colchicine in murine bone marrow-derived macrophages (BMDMs).To elucidate the underlying mechanism, RNA sequencing, biological and chemical inhibition assays, and Western blot, quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA), and immunohistochemical analyses were employed. Finally, type I interferon-dependent highly TB-susceptible A/J mice were challenged with virulent Mtb H37Rv, and the host-directed therapeutic effect of oral colchicine administration on bacterial burdens and lung inflammation was assessed 30 days postinfection (2.5 mgÁkg À1 every 2 days).Key Results: Colchicine reinforced the anti-Mtb activity of BMDMs without affecting cell viability, indicating that colchicine facilitated macrophage immune activation upon Mtb infection. The results from RNA sequencing, NLRP3 knockout BMDM, IL-1 receptor blockade, and immunohistochemistry analyses revealed that this unexpected intracellular anti-Mtb activity of colchicine was mediated through NLRP3-dependent IL-1β signalling and Cox-2-regulated PGE 2 production in macrophages. Consequently, the TB-susceptible A/J mouse model showed remarkable protection, with decreased bacterial loads in both the lungs and spleens of oral colchicine-treated mice, with significantly elevated Cox-2 expression at infection sites. Conclusions and Implications:The repurposing of colchicine against Mtb infection in this study highlights its unique function in macrophages upon Mtb infection and its novel potential use in treating TB as host-directed or adjunctive therapy.

Protein-energy restriction-induced lipid metabolism disruption causes stable-to-progressive disease shift in Mycobacterium avium-infected female mice

“…Western blot analysis was conducted as previously described. 32 Briefly, total protein was extracted from lung tissue using PRO-PREP protein extraction solution (#17081, INTRON Biotechnology, Seoul, South Korea) following the manufacturer's instructions. Proteins were quantified, and equal amounts were separated by SDS-PAGE, then transferred onto Immun-Blot™ PVDF membranes.…”

“…Sample sizes for this study were established based on prior research, including studies from our group. 32 , 33 , 34 , 35 An a priori power analysis was conducted to confirm the appropriateness of our sample sizes, targeting 80% power and a 0.05 alpha level. This analysis indicated that a minimum of three mice per group would suffice.…”

Host-directed therapy against mycobacterium tuberculosis infections with diabetes mellitus

“…Berbamine was shown to activate macrophage autophagy by modulating the ROS/Ca2+ axis, and could efficiently inhibit MTB, demonstrating the advantage of improving the efficacy or shortening the course of treatment in drug-resistant TB ( 114 ). The antigout drug colchicine enhanced macrophage resistance to MTB by modulating NLRP3-dependent IL-1β signaling and COX-2-mediated PGE2 production in macrophages ( 115 ).…”

Targeting Neutrophil Extracellular Traps in Gouty Arthritis: Insights into Pathogenesis and Therapeutic Potential

“…Colchicine has been a medicine widely used in GA for a long history. 183,184 The incidence of adverse reactions is high since the therapeutic dose of colchicine is close to the toxic dose. 185 For patients with acute gout attacks, it is recommended to accept colchicine treatment in the first dose of 1 mg, 0.5 mg after 1 h, and 0.5 mg after 12 h, with a frequency of once a day or twice a day.…”