Macrophage Phenotypic Switch Orchestrates the Inflammation and Repair/Regeneration Following Acute Pancreatitis

Abstract

Impaired or hyperactive pancreas regeneration after injury would cause exocrine insufficiency or recurrent/chronic pancreatitis and potentially carcinogenesis. Monocyte/Macrophage is a determinant during the pathogenesis of acute pancreatitis(AP), however little is known about the fate and role of these macrophages during the repair/regeneration phase. Using caerulein-induced AP model, we found M1 macrophages in acute inflammatory phase of AP were switched to M2-like macrophages during the regeneration of the pancreas. Depletion of macrophages at early or late regenerative stage dramatically blocked the ADM or delayed inflammation resolution, respectively. Moreover, M2 activation of macrophages was partially dependent on IL-4RA signaling, and macrophage-derived PI3K/AKT signaling facilitated inflammation resolution during acinar re-differentiation. Together, our findings illustrate a dynamic requirement for macrophages during AP repair / regeneration. Investigating the dynamic phenotype and role of macrophage helps us better understand the mechanism of pancreas regeneration, which would provide clues for novel therapeutic strategy. Funding Statement: This work was supported by Program for professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning No.TP2015007 (J.Xue); Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support No.20161312 (J.Xue); The Shanghai Youth Talent Support Program (J.Xue); Shanghai Rising-Star Program No.19QA1408300 (N.Ning); Natural Science Foundation of China No.81702938, No.81770628 and No. 81970553 (J.Xue), No.81802307(P.Lu). Declaration of Interests: All authors have declared that no conflict of interest exists. Ethics Approval Statement: Animal experiments were approved by the guidelines of the Ren Ji Hospital Institutional Animal Care and Ethics Committee.