Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis

Abstract

Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis, we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on IL-4 and IL-13 signaling and we show that mice lacking IL-4Rα, myeloid specific IL-4Rα, and IL-4/IL-13 were less susceptible to pancreatic fibrosis. Furthermore, we demonstrate that mouse and human pancreatic stellate cells (PSCs) are a source of IL-4/IL-13. Notably, we show that pharmacologic inhibition of IL-4/IL-13 in human ex-vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis. We identify a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage alternative activation. Our study challenges and identifies pathways involved in cross talk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression.

Emodin Bidirectionally Modulates Macrophage Polarization and Epigenetically Regulates Macrophage Memory

“…M2 macrophages contribute to lung inflammation and damage in allergy and asthma (13,14). They have also been shown to impair tissue functions through promoting fibrosis (23). M2 macrophage infiltration correlates with increased cancer growth and metastasis in multiple types of cancer (14,24).…”

Immune modulation in acute and chronic pancreatitis

“…Notably, the macrophages are found in proximity to areas of fibrosis (16,98). Lipopolysaccharide (LPS)-activated macrophages stimulate pancreatic stellate cell (PSC) activation and promote collagen and fibronectin synthesis in cultured PSCs (77).…”

“…However, a role for macrophage TLR4 in chronic pancreatitis remains to be defined. Unlike in acute pancreatitis, alternatively activated macrophages predominate in chronic pancreatitis and inhibiting macrophage IL-4Rα signalling decreases pancreatic stellate cell activation, fibrosis, and disease progression in cerulein-induced mouse model of chronic pancreatitis (98). Alcohol feeding and cerulein treatment in mice had an additive effect in increasing arginase expressing macrophages in the pancreas (95) …”

“…Indeed, the reduction of peripheral blood CD4 + T lymphocytes is associated with persistent organ failure during acute pancreatitis (100). In contrast in chronic pancreatitis, an increase in immune cell infiltration, mainly T cells and macrophages, is observed (21,51,98). In the dibutyltin dichloride (DBTC) rat model of chronic pancreatitis, increase in both CD4+ and CD8+ T cells was observed and over time characterized by a decrease in CD4+/CD8+ T cell ratio due to a continuous rise in infiltrating CD8+ T cells (85).…”

“…CCR2 ligands are also elevated in experimental chronic pancreatitis and competitive bone marrow studies show a role for CCR2 in monocyte/macrophage accumulation in the chronically inflamed pancreas (98). However, a worse disease outcome was reported in ceruleininduced chronic pancreatitis in CCR2 knockout mice as compared to their wild type counterparts (59).…”