Ly-6Chi INFLAMMATORY MONOCYTES GOVERN THE SEVERITY OF CAERULEIN- AND TAUROCHOLATE-INDUCED ACUTE PANCREATITIS IN MICE

Abstract

Background: Recent reports have shown that circulating monocytes exist in at least 2 phenotypic subsets- i.e. resident (Ly-6Clo) and inflammatory (Ly-6Chi) monocytes. Inflammatory monocytes traffic to, and enter, sites of inflammation in response to appropriate stimuli and, as inflammatory tissue macrophages, they play key pro-inflammatory roles. We have previously shown that targeted and conditional monocyte/macrophage depletion reduces the severity of caerulein and taurocholate-induced pancreatitis. Aim: To identify the monocyte subset that regulates the severity of pancreatitis and to examine its route of trafficking. Methods: Mice expressing the human diphtheria toxin receptor (hDTR) coupled to the CD11b promoter were pre-treated with diphtheria toxin (DT) to deplete monocytes/ macrophages and, 24 hrs later, caerulein or taurocholate-induced pancreatitis was elicited. Twelve hrs after the start of pancreatitis induction, the mice were infused with peripheral blood mononuclear cells (PBMC) or bone marrow cells (BMC) obtained from naive donors. In trafficking studies, donor cells were pre-labeled by incubation with CFSE. Pancreatitis severity and the fate of adoptively transferred PBMC or BMC were evaluated using standard histological methods and flow cytometry. Results: Ly-6Chi cells were (a) depleted in the pancreas during pancreatitis, (b) present in the adoptive transfer mixture, and (c) found in circulating blood after adoptive transfer of either PBMC or BMC. Pancreatitis severity was restored by adoptive transfer of either PBMC or BMC but CFSE-labeled Ly-6Chi cells were found in the pancreas only after adoptive transfer of BMC. Removal of Ly-6Chi cells from the adoptive transfer pool prevented restoration of pancreatitis severity after adoptive transfer. Conclusions: Pancreatitis severity is governed by inflammatory Ly-6Chi monocytes that are mobilized from the bone marrow but act after trafficking to the pancreas.