MicroRNA-206 promotes the recruitment of CD8+ T cells by driving M1 polarisation of Kupffer cells
Menée à l'aide d'un modèle murin de carcinome hépatocellulaire, cette étude met en évidence un mécanisme par lequel le microARN-206, en induisant la polarisation M1 des cellules de Kupffer, favorise le recrutement des lymphocytes T CD8+ et prévient la carcinogenèse
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.All data relevant to the study are included in the article or uploaded as supplementary information.