Dissecting the role of hepatic Nfκb1 in inflammation and ageing

Abstract

The NF-κB family is a group of 5 subunits functioning as transcription factors in a variety of important cellular pathways, including inflammation, cell proliferation and cancer. They work as hetero and homodimers to regulate the gene expression. In particular, Nfκb1 can form homodimers and recruit epigenetic modifiers at gene promoters, modulating their expression in both directions, depending on the coupling co-factor. Previous studies have shown that Nfκb1-/- cells presented higher expression of inflammatory genes compared to normal cells (wt). Also, mice globally lacking Nfκb1 aged faster compared to their wt littermates and with particular attention to the liver, they develop more tumours. I wanted to dissect the contribution of Nfκb1 to inflammation and ageing in a specific cell type, namely hepatocytes. To do so, I used a Cre-LoxP system in a mouse model to selectively knock out Nfκb1 in hepatocytes. RNA sequencing in primary murine hepatocytes suggested that upon acute treatment with LPS, Nfκb1-/- hepatocytes failed to repress the expression of a subset of inflammatory genes at the resolution stage. In a more complex model such as Precision Cut Liver Slices, Nfκb1-/- slices did not show the same trend observed in primary cells, probably due to the compensatory mechanisms ongoing in other cell types. Lastly, aged Nfκb1-/- mice presented more steatosis and a greater number of immune cells aggregates resembling ectopic lymphoid structures. Interestingly, the same mice presented extensive damage in the kidneys, despite expressing Nfκb1. I hypothesise that because of their more inflamed phenotype, hepatocytes lacking Nfκb1 secrete more inflammatory mediators that damage the cells and the whole organ as the mice age. This damage is spread through soluble factors in the blood stream, causing the loss of architecture and function in organs expressing Nfκb1, such as the kidneys. These results support the idea that Nfκb1 might be dispensable to induce an inflammatory response, but it is necessary to limit inflammation in hepatocytes in order to prevent the onset of chronic inflammation with accelerated ageing.