Macrophage phenotypic switch orchestrates the inflammation and repair/regeneration following acute pancreatitis injury.

BACKGROUND

Impaired or hyperactive pancreas regeneration after injury would cause exocrine insufficiency or recurrent / chronic pancreatitis and potentially carcinogenesis. Macrophages are the most abundant immune cells in the regenerative pancreas, however their phenotype and role remain poorly defined.

METHOD

Using caerulein-induced acute pancreatitis (AP) model, we examined the dynamic landscape of pancreatic macrophages throughout the acute inflammation to regeneration phases by flow cytometric and RNA-seq analyses. Liposome depletion of macrophages, Il4ra mice as well as inhibitors were used to elucidate the role and regulatory mechanism of macrophages during pancreatic regeneration.

FINDINGS

We found that M1 macrophages dominated in the pro-inflammatory phase of AP, while M2-like macrophages dominated during pancreas repair/regeneration. Depletion of macrophages at early or late regenerative stage dramatically blocked the acinar-ductal metaplasia (ADM) or delayed inflammation resolution, respectively. Moreover, alternative activation of macrophages was partially dependent on IL-4RA signaling, and ECM/AKT activation in pancreatic macrophages facilitated inflammation resolution during tissue regeneration.

INTERPRETATION

Our findings illustrate a dynamic phenotype and function of macrophages during AP repair/regeneration, helping us better understand the mechanism of pancreatic regeneration and providing clues for novel therapeutic strategy.