Monocytes Infiltrate the Pancreas via the MCP-1/CCR2 Pathway and Differentiate into Stellate Cells

Abstract

Recent studies have shown that monocytes possess pluripotent plasticity. We previously reported that monocytes could differentiate into hepatic stellate cells. Although stellate cells are also present in the pancreas, their origin remains unclear. An accumulation of enhanced green fluorescent protein (EGFP)+CD45– cells was observed in the pancreases and livers of chimeric mice, which were transplanted with a single hematopoietic stem cell isolated from EGFP-transgenic mice and treated with carbon tetrachloride (CCl4). Because the vast majority of EGFP+CD45– cells in the pancreas expressed stellate cell-associated antigens such as vimentin, desmin, glial fibrillary acidic protein, procollagen-I, and α-smooth muscle actin, they were characterized as pancreatic stellate cells (PaSCs). EGFP+ PaSCs were also observed in CCl4-treated mice adoptively transferred with monocytes but not with other cell lineages isolated from EGFP-transgenic mice. The expression of monocyte chemoattractant protein-1 (MCP-1) and angiotensin II (Ang II) increased in the pancreas of CCl4-treated mice and their respective receptors, C-C chemokine receptor 2 (CCR2) and Ang II type 1 receptor (AT1R), were expressed on Ly6Chigh monocytes isolated from EGFP-transgenic mice. We examined the effect of an AT1R antagonist, irbesartan, which is also a CCR2 antagonist, on the migration of monocytes into the pancreas. Monocytes migrated toward MCP-1 but not Ang II in vitro. Irbesartan inhibited not only their in vitro chemotaxis but also in vivo migration of adoptively transferred monocytes from peripheral blood into the pancreas. Irbesartan treatment significantly reduced the numbers of EGFP+F4/80+CCR2+ monocytic cells and EGFP+ PaSCs in the pancreas of CCl4-treated chimeric mice receiving EGFP+ bone marrow cells. A specific CCR2 antagonist RS504393 inhibited the occurrence of EGFP+ PaSCs in injured mice. We propose that CCR2+ monocytes migrate into the pancreas possibly via the MCP-1/CCR2 pathway and give rise to PaSCs.

Replicative capacity of β-cells and type 1 diabetes

“…Macrophage-produced growth factors and cytokines regulated SMAD7 expression in β-cells and subsequently influenced proliferation [53,68,69]. …”

The pancreas anatomy conditions the origin and properties of resident macrophages

“…Mouse models of type 2 diabetes showed changes of islet macrophages to a proinflammatory profile (M1; Cucak et al, 2014 ; Westwell-Roper et al, 2014 ). Concerning the exocrine pancreas, macrophages were examined mostly in pathological situations (inflammation after ductal ligation, carbon tetrachloride–induced pancreatitis, and experimental pancreatic cancer) and limited studies under steady state ( Yin et al, 2011 ; Ino et al, 2014 ; Xiao et al, 2014 ).…”

Multifunctional role of pancreatic stellate cells in pancreatic cancer

“…Although the origin of PSCs is not clear, it was demonstrated that a proportion of PSCs originate from bone marrow and replenish PSCs in the pancreas (38). In addition, Ino et al (39) showed that chemokine receptor type 2 (CCR2 + ) monocytes migrate from the bone marrow and transform into PSCs through the monocyte chemoattractant protein-1 (MCP-1)/CCR2 pathway. The monocyte lineage origin of PSC is also supported by the expression of monocyte specific marker α-naphthyl butyrate esterase (ANBE) (40).…”