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 transposon to induce HCC. Mini-circle and 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 (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 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.