Macrophage dynamics are regulated by local macrophage proliferation and monocyte recruitment in injured pancreas

Eur J Immunol. 2015 May;45(5):1482-93. doi: 10.1002/eji.201445013. Epub 2015 Mar 19.

Abstract

Pancreas injury by partial duct ligation (PDL) activates a healing response, encompassing β-cell neogenesis and proliferation. Macrophages (MΦs) were recently shown to promote β-cell proliferation after PDL, but they remain poorly characterized. We assessed myeloid cell diversity and the factors driving myeloid cell dynamics following acute pancreas injury by PDL. In naive and sham-operated pancreas, the myeloid cell compartment consisted mainly of two distinct tissue-resident MΦ types, designated MHC-II(lo) and MHC-II(hi) MΦs, the latter being predominant. MHC-II(lo) and MHC-II(hi) pancreas MΦs differed at the molecular level, with MHC-II(lo) MΦs being more M2-activated. After PDL, there was an early surge of Ly6C(hi) monocyte infiltration in the pancreas, followed by a transient MHC-II(lo) MΦ peak and ultimately a restoration of the MHC-II(hi) MΦ-dominated steady-state equilibrium. These intricate MΦ dynamics in PDL pancreas depended on monocyte recruitment by C-C chemokine receptor 2 and macrophage-colony stimulating factor receptor as well as on macrophage-colony stimulating factor receptor-dependent local MΦ proliferation. Functionally, MHC-II(lo) MΦs were more angiogenic. We further demonstrated that, at least in C-C chemokine receptor 2-KO mice, tissue MΦs, rather than Ly6C(hi) monocyte-derived MΦs, contributed to β-cell proliferation. Together, our study fully characterizes the MΦ subsets in the pancreas and clarifies the complex dynamics of MΦs after PDL injury.

Keywords: MΦ activation; MΦ heterogeneity; MΦ proliferation; Pancreas inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / metabolism
  • Cell Movement / immunology
  • Cell Proliferation
  • Cellular Microenvironment / immunology
  • Histocompatibility Antigens Class II / metabolism
  • Ligation
  • Macrophage Activation
  • Macrophages / immunology*
  • Macrophages / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Monocytes / immunology*
  • Monocytes / pathology*
  • Myeloid Cells / classification
  • Myeloid Cells / immunology
  • Myeloid Cells / pathology
  • Pancreas / immunology*
  • Pancreas / injuries*
  • Pancreas / pathology
  • Pancreatic Ducts / injuries
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism
  • Regeneration / immunology

Substances

  • Antigens, Ly
  • Histocompatibility Antigens Class II
  • Ly-6C antigen, mouse
  • Receptor, Macrophage Colony-Stimulating Factor