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Host-directed anti-mycobacterial activity of colchicine, an anti-gout drug, via strengthened host innate resistance reinforced by the IL-1β/PGE 2 axis

Authors
 Kee Woong Kwon  ;  Lee-Han Kim  ;  Soon Myung Kang  ;  Ju Mi Lee  ;  Eunsol Choi  ;  Jiyun Park  ;  Jung Joo Hong  ;  Sung Jae Shin 
Citation
 BRITISH JOURNAL OF PHARMACOLOGY, Vol.179(15) : 3951-3969, 2022-08 
Journal Title
BRITISH JOURNAL OF PHARMACOLOGY
ISSN
 0007-1188 
Issue Date
2022-08
MeSH
Animals ; Colchicine / metabolism ; Colchicine / pharmacology ; Cyclooxygenase 2 / metabolism ; Dinoprostone / pharmacology ; Mice ; Mycobacterium tuberculosis* ; NLR Family, Pyrin Domain-Containing 3 Protein / metabolism ; Tuberculosis*
Keywords
IL-1β ; Mycobacterium tuberculosis ; PGE2 ; colchicine ; host-directed therapy ; innate immunity ; macrophage
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 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-1β signalling and Cox-2-regulated PGE2 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.
Full Text
https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15838
DOI
10.1111/bph.15838
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Others (기타) > 1. Journal Papers
Yonsei Authors
Kwon, Kee Woong(권기웅)
Kim, Lee-Han(김이한)
Shin, Sung Jae(신성재) ORCID logo https://orcid.org/0000-0003-0854-4582
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/189483
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