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

被引：7

作者：

Kwon, Kee Woong ^{[1
,2
]}

Kim, Lee-Han ^{[1
,2
]}

Kang, Soon Myung ^{[1
,2
]}

Lee, Ju Mi ^{[1
,2
]}

Choi, Eunsol ^{[1
,2
]}

Park, Jiyun ^{[1
,2
]}

Hong, Jung Joo ^{[3
,4
]}

Shin, Sung Jae ^{[1
,2
]}

机构：

[1] Yonsei Univ, Coll Med, Brain Korea 21 Project Grad Sch Med Sci, Dept Microbiol, Seoul, South Korea

[2] Yonsei Univ, Coll Med, Brain Korea 21 Project Grad Sch Med Sci, Inst Immunol & Immunol Dis, Seoul, South Korea

[3] Korea Res Inst Bioscience & Biotechnol, Natl Primate Res Ctr, Cheongju, South Korea

[4] Korea Univ Sci & Technol UST, KRIBB Sch Biosci, Daejeon, South Korea

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2022年 / 179卷 / 15期

基金：

新加坡国家研究基金会;

关键词：

colchicine; host-directed therapy; IL-1; beta; innate immunity; macrophage; Mycobacterium tuberculosis; PGE(2); MYCOBACTERIUM-TUBERCULOSIS; NLRP3; INFLAMMASOME; CONCISE GUIDE; RECEPTOR; THERAPY; MICE; CYCLOOXYGENASE-2; SUSCEPTIBILITY; HYPERURICEMIA; MACROPHAGES;

D O I：

10.1111/bph.15838

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 post-infection (2.5 mg-kg(-1) 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-1 beta 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.

引用

页码：3951 / 3969

页数：19