Macrophage WNT signalling in liver disease and regeneration

Abstract

Liver disease is still a clinical challenge. Even though the liver has a regenerative capacity, it can be impaired during acute or chronic injuries.

Paracetamol overdose is the leading cause of acute liver injury in the US and UK. It can progress to liver failure in which liver transplantation is the sole treatment. Chronic liver injury also represents a clinical burden that can progress to cirrhosis and cancer. As there are no effective treatments to cure these diseases, there is the need to seek alternative treatments. Macrophage targeting is a promising approach to treat liver injured patients. WNT signalling has been shown to play important roles in liver regeneration and cancer progression. Since macrophages are a source of WNTs implicated in several diseases, it was hypothesised that macrophage WNT signalling could be modulated to stop disease progression or enhance liver regeneration. Two different in vivo models were used to study the role of macrophage WNT signalling in liver disease and regeneration. The first model was a Ctnnb1 deletion on Csf1r-expressing cells (referred to as β-catenin KO), in which myeloid cells did not respond to WNTs. The second model was a Porcupine deletion on Csf1r-expressing cells (Porcn KO), in which myeloid cells did not secrete WNTs. To determine the role of β-catenin signalling in macrophage polarisation, β-catenin WT and KO bone marrow-derived macrophages were polarised towards tissue repair-like or inflammatory-like phenotypes and submitted for bulk RNA-Sequencing.

Deletion of β-catenin resulted in minimal changes that suggested a mild macrophage phenotype. The macrophage response to WNTs or their WNT secretion was not essential in a paracetamol overdose model in mice. WT and KO mice regenerated similarly and did not have any differences in macrophage infiltration into injured sites. In a model of chronic liver injury by DDC diet, macrophage WNT signalling played a role in disease progression. Even though macrophages did not respond to WNTs, inhibition of macrophage WNT secretion resulted in increased fibrotic levels on Porcn KO mice. Progression to this disease can cause cholangiocarcinoma. Thus, using a cholangiocarcinoma model, Porcn KO mice suggested to have a lower tumour load compared to their littermate controls. However, macrophages were not responding to WNTs during cancer progression. These studies showed that the liver repair mechanisms are injury dependent and while macrophage WNT signalling is playing a role in some conditions, further studies are needed to understand the pathways involved to develop effective treatments.