CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion

Abstract

Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b(+)Gr-1(low) macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b(+)/Gr-1(-) and CD11b(+)/Gr-1(high) cells, but not CD11b(+)/Gr-1(low) cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b(+)-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

Bone marrow-derived macrophages distinct from tissue-resident macrophages play a pivotal role in Concanavalin A-induced murine liver injury via CCR9 axis

“…C57BL/6 (wild-type: WT) CD45.2 mice were purchased from CLEA Japan (Tokyo, Japan). C57BL/6 CD45.1 mice and Ccr2 − / − mice were described previously 29 50 . All mice were maintained under specific pathogen-free conditions in the Animal Care Facility of Keio University School of Medicine.…”

Dachaihu decoction ameliorates pancreatic fibrosis by inhibiting macrophage infiltration in chronic pancreatitis

“…Recent studies have highlighted the role of macrophages in promoting wound healing and fibrosis[ 5 , 6 ]. Large numbers of macrophages have been observed around areas of pancreatic injury in rat models of CP[ 7 , 8 ]. Detlefsen and colleagues[ 9 ] demonstrated that many infiltration macrophages are also found in the pancreas of alcoholic CP patients, which facilitate fibrosis formation by producing transforming growth factor (TGF)-β and platelet derived growth factor (PDGF)-β.…”

Immune modulation in acute and chronic pancreatitis

“…Results form CCR2 deficient mice were also consistent with these findings (59). CCR5 deficient mice on the other hand had exacerbated cerulein-induced acute pancreatitis, and may have been due to the fact that CCR5 knock out mice had increased CCL2/MCP-1 and other monocyte/macrophage chemoattractant production that may have accounted for the pronounced pancreatic inflammation (58).…”

“…However, a worse disease outcome was reported in ceruleininduced chronic pancreatitis in CCR2 knockout mice as compared to their wild type counterparts (59). Thus further studies are needed to determine the role for CCR2 in chronic pancreatitis.…”