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MicroRNA-206 promotes the recruitment of CD8(+) T cells by driving M1 polarisation of Kupffer cells

OBJECTIVE: Kupffer cells (KCs) protect against hepatocellular carcinoma (HCC) by communicating with other immune cells. However, the underlying mechanism(s) of this process is incompletely understood. DESIGN: FVB/NJ mice were hydrodynamically injected with AKT/Ras and Sleeping Beauty transposon to i...

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Autores principales: Liu, Ningning, Wang, Xiaomei, Steer, Clifford John, Song, Guisheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279850/
https://www.ncbi.nlm.nih.gov/pubmed/34706869
http://dx.doi.org/10.1136/gutjnl-2021-324170
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author Liu, Ningning
Wang, Xiaomei
Steer, Clifford John
Song, Guisheng
author_facet Liu, Ningning
Wang, Xiaomei
Steer, Clifford John
Song, Guisheng
author_sort Liu, Ningning
collection PubMed
description OBJECTIVE: Kupffer cells (KCs) protect against hepatocellular carcinoma (HCC) by communicating with other immune cells. However, the underlying mechanism(s) of this process is incompletely understood. DESIGN: FVB/NJ mice were hydrodynamically injected with AKT/Ras and Sleeping Beauty transposon to induce HCC. Mini-circle and Sleeping Beauty were used to overexpress microRNA-206 in KCs of mice. Flow cytometry and immunostaining were used to evaluate the change in the immune system. RESULTS: Hydrodynamic injection of AKT/Ras into mice drove M2 polarisation of KCs and depletion of cytotoxic T cells (CTLs) and promoted HCC development. M1-to-M2 transition of KCs impaired microRNA-206 biogenesis. By targeting Klf4 (kruppel like factor 4) and, thereby, enhancing the production of M1 markers including C-C motif chemokine ligand 2 (CCL2), microRNA-206 promoted M1 polarisation of macrophages. Indeed, microRNA-206-mediated increase of CCL2 facilitated hepatic recruitment of CTLs via CCR2. Disrupting each component of the KLF4/CCL2/CCR2 axis impaired the ability of microRNA-206 to drive M1 polarisation of macrophages and recruit CTLs. In AKT/Ras mice, KC-specific expression of microRNA-206 drove M1 polarisation of KCs and hepatic recruitment of CTLs and fully prevented HCC, while 100% of control mice died from HCC. Disrupting the interaction between microRNA-206 and Klf4 in KCs and depletion of CD8(+) T cells impaired the ability of miR-206 to prevent HCC. CONCLUSIONS: M2 polarisation of KCs is a major contributor of HCC in AKT/Ras mice. MicroRNA-206, by driving M1 polarisation of KCs, promoted the recruitment of CD8(+) T cells and prevented HCC, suggesting its potential use as an immunotherapeutic approach.
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spelling pubmed-92798502022-08-01 MicroRNA-206 promotes the recruitment of CD8(+) T cells by driving M1 polarisation of Kupffer cells Liu, Ningning Wang, Xiaomei Steer, Clifford John Song, Guisheng Gut Hepatology OBJECTIVE: Kupffer cells (KCs) protect against hepatocellular carcinoma (HCC) by communicating with other immune cells. However, the underlying mechanism(s) of this process is incompletely understood. DESIGN: FVB/NJ mice were hydrodynamically injected with AKT/Ras and Sleeping Beauty transposon to induce HCC. Mini-circle and Sleeping Beauty were used to overexpress microRNA-206 in KCs of mice. Flow cytometry and immunostaining were used to evaluate the change in the immune system. RESULTS: Hydrodynamic injection of AKT/Ras into mice drove M2 polarisation of KCs and depletion of cytotoxic T cells (CTLs) and promoted HCC development. M1-to-M2 transition of KCs impaired microRNA-206 biogenesis. By targeting Klf4 (kruppel like factor 4) and, thereby, enhancing the production of M1 markers including C-C motif chemokine ligand 2 (CCL2), microRNA-206 promoted M1 polarisation of macrophages. Indeed, microRNA-206-mediated increase of CCL2 facilitated hepatic recruitment of CTLs via CCR2. Disrupting each component of the KLF4/CCL2/CCR2 axis impaired the ability of microRNA-206 to drive M1 polarisation of macrophages and recruit CTLs. In AKT/Ras mice, KC-specific expression of microRNA-206 drove M1 polarisation of KCs and hepatic recruitment of CTLs and fully prevented HCC, while 100% of control mice died from HCC. Disrupting the interaction between microRNA-206 and Klf4 in KCs and depletion of CD8(+) T cells impaired the ability of miR-206 to prevent HCC. CONCLUSIONS: M2 polarisation of KCs is a major contributor of HCC in AKT/Ras mice. MicroRNA-206, by driving M1 polarisation of KCs, promoted the recruitment of CD8(+) T cells and prevented HCC, suggesting its potential use as an immunotherapeutic approach. BMJ Publishing Group 2022-08 2021-10-27 /pmc/articles/PMC9279850/ /pubmed/34706869 http://dx.doi.org/10.1136/gutjnl-2021-324170 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Hepatology
Liu, Ningning
Wang, Xiaomei
Steer, Clifford John
Song, Guisheng
MicroRNA-206 promotes the recruitment of CD8(+) T cells by driving M1 polarisation of Kupffer cells
title MicroRNA-206 promotes the recruitment of CD8(+) T cells by driving M1 polarisation of Kupffer cells
title_full MicroRNA-206 promotes the recruitment of CD8(+) T cells by driving M1 polarisation of Kupffer cells
title_fullStr MicroRNA-206 promotes the recruitment of CD8(+) T cells by driving M1 polarisation of Kupffer cells
title_full_unstemmed MicroRNA-206 promotes the recruitment of CD8(+) T cells by driving M1 polarisation of Kupffer cells
title_short MicroRNA-206 promotes the recruitment of CD8(+) T cells by driving M1 polarisation of Kupffer cells
title_sort microrna-206 promotes the recruitment of cd8(+) t cells by driving m1 polarisation of kupffer cells
topic Hepatology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279850/
https://www.ncbi.nlm.nih.gov/pubmed/34706869
http://dx.doi.org/10.1136/gutjnl-2021-324170
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