# IL‐4/STAT6‐signaling Influences Local Inflammation and Regeneration Processes During Acute Pancreatitis and Promotes Fibrosis by a Direct Activation of Pancreatic Fibroblasts During Chronic Pancreatitis

## TL;DR

This study shows that IL-4/STAT6 signaling reduces inflammation and supports healing in acute pancreatitis but has limited effect on fibrosis in chronic pancreatitis.

## Contribution

The study reveals the dual role of IL-4/STAT6 signaling in modulating inflammation and regeneration in acute pancreatitis and its limited impact on fibrosis in chronic pancreatitis.

## Key findings

- IL-4/STAT6 signaling suppresses pro-inflammatory responses and promotes acinar cell regeneration in acute pancreatitis.
- STAT6 deletion leads to mixed macrophage phenotypes and prolonged inflammation in pancreatitis.
- STAT6 signaling directly activates fibroblasts to produce extracellular matrix components but only moderately reduces fibrosis in chronic pancreatitis.

## Abstract

In both acute and chronic pancreatitis, the local pancreatic immune response has a significant influence on the course of the disease. Utilizing a murine model deficient in STAT6, we demonstrate that the IL‐4/IL‐13/STAT6‐signaling pathway, which is a central component of the type 2 immune response, is rapidly activated during acute pancreatitis, thereby suppressing the pro‐inflammatory reaction and dampening the inflammation‐driven disease severity. The deletion of STAT6 in Stat6‐/‐ knock‐out mice surprisingly do not affect the numbers of CD206+ macrophages nor the release of TGF‐β. Notably, Stat6‐/‐ macrophages in CP are characterized by a high expression of the M2 markers Fizz1, Ym1 and Arg1, but also showed pro‐inflammatory properties, indicated by the expression of Nos2, Il1b and Mmp9. This mixed functional phenotype corresponded to a prolonged pro‐inflammatory response in pancreatitis and an impairment of acinar cell regeneration. STAT6‐signaling directly stimulated the production of selected extracellular matrix components in pancreatitis associated fibroblasts (PAFs). However, deletion of STAT6 only moderately reduced the fibrosis during chronic pancreatitis. Our study demonstrates that the IL‐4/IL‐13 STAT6‐signaling pathway represents a critical regulatory mechanism suppressing the inflammation and stimulating wound healing and organ regeneration during acute and chronic pancreatitis.

IL‐4/IL‐13/STAT6 signaling plays a crucial for the suppression of pro‐inflammation during acute pancreatitis and supports acinar cell regeneration but has only minor impact on fibrogenesis during chronic form of the disease. IL‐4/IL‐13 induce the expression of certain collagens directly in pancreatic fibroblasts via STAT6 activation, whereas alternative macrophage polarization is compensated in the absence of STAT6 during chronic pancreatitis.