The cell cycle protein Cyclin E1 mediates pro-inflammatory signals in a mouse model of acute hepatitis and in primary macrophages

Cyclin E1 mediates important steps within the cell cycle. We previously identified unexpected essential functions of Cyclin E1 for liver fibrogenesis, inflammation and hepatocarcinogenesis. However, the effector cells of Cyclin E1 in the liver have not yet been fully identified. Here, we investigated the role of Cyclin E1 in immune cells during acute liver inflammation.

We used constitutive Cyclin E1 knockout (Ccne1-/-) mice and the Concanavalin A (ConA) model of immune-mediated hepatitis. Moreover, we investigated bone marrow-derived macrophages (BMDM) from Ccne1-/- and WT mice and performed knockdown experiments in a macrophage cell line using anti-Ccne1 siRNA encapsulated in lipid nanoparticles (LNP).

Ccne1-/- mice showed improved survival after ConA-treatment, which was associated with significantly reduced liver necrosis. Loss of Ccne1 was related to down-regulation of pro-inflammatory mediators such as interleukin-6 (IL6), tumor necrosis factor alpha (TNF), and CC-chemokine ligand 2 (CCL2). We tested the impact of Ccne1 deletion in pro-inflammatory polarized BMDMs. Ccne1-/- BMDMs also revealed reduced IL6 expression compared to WT controls. Importantly, Ccne1-/- BMDMs did not show any changes in cell cycle progression or in myeloid progenitor cell to macrophage differentiation. These findings were validated in an interventional approach. To this end pro-inflammatory polarized J774A.1 cells were treated with anti-Ccne1 siRNA-LNPs, which was sufficient to significantly reduce IL6 expression.

Altogether, Cyclin E1 mediates a novel, pro-inflammatory function in the liver, which is fully independent from its canonical role as a cell cycle mediator. Thus, inhibition of Cyclin E1 could be a promising approach for treatment of acute immune-mediated hepatitis.

Publication History

Article published online:
23 January 2024