# MK2 Inhibition as a Novel Treatment for Fibrosis in Primary Sclerosing Cholangitis via an IL-22-Dependent Mechanism

## TL;DR

This study shows that inhibiting MK2 reduces liver inflammation and fibrosis in a mouse model of PSC, possibly through increased IL-22 and other anti-inflammatory cytokines.

## Contribution

The paper introduces MK2 inhibition as a novel therapeutic strategy for PSC fibrosis via an IL-22-dependent mechanism.

## Key findings

- MK2 inhibition reduced hepatic inflammation and fibrosis in MDR2 knockout mice.
- MK2 inhibition increased IL-22, IL-10, and G-CSF while decreasing fibrotic markers like collagen 1A1 and fibronectin.
- IL-22 treatment alone also improved inflammation and fibrosis in the mouse model.

## Abstract

Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by bile duct inflammation and fibrosis, leading to cirrhosis and liver failure. Current therapies are limited to symptom management, with no approved treatments targeting fibrosis. We have identified the MAP kinase-activated protein kinase 2 (MK2) pathway as a potential therapeutic target for treating PSC due to its role in promoting inflammatory cytokine production and activation of fibroblasts. Thus, MDR2 knockout mice were treated therapeutically with MK2 inhibitors, which led to significantly reduced hepatic inflammation and fibrosis. Liver enzymes, collagen 1A1, and fibronectin were decreased in serum with MK2 inhibitor treatment. Furthermore, the production of IL-6, TNFα, CXCL5, collagen 1A1, and fibronectin was decreased in liver tissues and liver stellate cells, whereas the production of IL-10, G-CSF, and IL-22 was increased. MDR2KO mice treated with IL-22 also showed improvements in inflammation and fibrosis, along with increased IL-10 and G-CSF production. Taken together, we identified both a direct mechanism of MK2 regulation of fibrotic factors and an indirect cytokine-mediated mechanism whereby the levels of IL-22, IL-10, and G-CSF were increased with MK2 inhibition and contributed to decreased levels of fibrotic factors. These data suggest that the MK2 pathway is a promising treatment target for PSC.