PMID- 35301712 OWN - NLM STAT- MEDLINE DCOM- 20220708 LR - 20220718 IS - 1476-5381 (Electronic) IS - 0007-1188 (Linking) VI - 179 IP - 15 DP - 2022 Aug TI - Host-directed anti-mycobacterial activity of colchicine, an anti-gout drug, via strengthened host innate resistance reinforced by the IL-1beta/PGE(2) axis. PG - 3951-3969 LID - 10.1111/bph.15838 [doi] AB - 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-1beta 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. CI - (c) 2022 The British Pharmacological Society. FAU - Kwon, Kee Woong AU - Kwon KW AUID- ORCID: 0000-0002-6259-855X AD - Department of Microbiology and Institute for Immunology and Immunological Disease, Brain Korea 21 Project for the Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South Korea. FAU - Kim, Lee-Han AU - Kim LH AUID- ORCID: 0000-0003-3402-1769 AD - Department of Microbiology and Institute for Immunology and Immunological Disease, Brain Korea 21 Project for the Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South Korea. FAU - Kang, Soon Myung AU - Kang SM AD - Department of Microbiology and Institute for Immunology and Immunological Disease, Brain Korea 21 Project for the Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South Korea. FAU - Lee, Ju Mi AU - Lee JM AUID- ORCID: 0000-0002-3396-7838 AD - Department of Microbiology and Institute for Immunology and Immunological Disease, Brain Korea 21 Project for the Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South Korea. FAU - Choi, Eunsol AU - Choi E AD - Department of Microbiology and Institute for Immunology and Immunological Disease, Brain Korea 21 Project for the Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South Korea. FAU - Park, Jiyun AU - Park J AD - Department of Microbiology and Institute for Immunology and Immunological Disease, Brain Korea 21 Project for the Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South Korea. FAU - Hong, Jung Joo AU - Hong JJ AD - National Primate Research Centre, Korea Research Institute of Bioscience and Biotechnology, Cheongju, South Korea. AD - KRIBB School of Bioscience, Korea University of Science & Technology (UST), Daejeon, South Korea. FAU - Shin, Sung Jae AU - Shin SJ AUID- ORCID: 0000-0003-0854-4582 AD - Department of Microbiology and Institute for Immunology and Immunological Disease, Brain Korea 21 Project for the Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, South Korea. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220407 PL - England TA - Br J Pharmacol JT - British journal of pharmacology JID - 7502536 RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - K7Q1JQR04M (Dinoprostone) RN - SML2Y3J35T (Colchicine) SB - IM MH - Animals MH - Colchicine/metabolism/pharmacology MH - Cyclooxygenase 2/metabolism MH - Dinoprostone/pharmacology MH - Mice MH - *Mycobacterium tuberculosis MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - *Tuberculosis OTO - NOTNLM OT - IL-1beta OT - Mycobacterium tuberculosis OT - PGE2 OT - colchicine OT - host-directed therapy OT - innate immunity OT - macrophage EDAT- 2022/03/19 06:00 MHDA- 2022/07/09 06:00 CRDT- 2022/03/18 05:44 PHST- 2022/03/02 00:00 [revised] PHST- 2021/09/06 00:00 [received] PHST- 2022/03/08 00:00 [accepted] PHST- 2022/03/19 06:00 [pubmed] PHST- 2022/07/09 06:00 [medline] PHST- 2022/03/18 05:44 [entrez] AID - 10.1111/bph.15838 [doi] PST - ppublish SO - Br J Pharmacol. 2022 Aug;179(15):3951-3969. doi: 10.1111/bph.15838. Epub 2022 Apr 7.