The scavenger receptor MARCO modulates TLR-induced responses in dendritic cells

PLoS One. 2014 Aug 4;9(8):e104148. doi: 10.1371/journal.pone.0104148. eCollection 2014.

Abstract

The scavenger receptor MARCO mediates macrophage recognition and clearance of pathogens and their polyanionic ligands. However, recent studies demonstrate MARCO expression and function in dendritic cells, suggesting MARCO might serve to bridge innate and adaptive immunity. To gain additional insight into the role of MARCO in dendritic cell activation and function, we profiled transcriptomes of mouse splenic dendritic cells obtained from MARCO deficient mice and their wild type counterparts under resting and activating conditions. In silico analysis uncovered major alterations in gene expression in MARCO deficient dendritic cells resulting in dramatic alterations in key dendritic cell-specific pathways and functions. Specifically, changes in CD209, FCGR4 and Complement factors can have major consequences on DC-mediated innate responses. Notably, these perturbations were magnified following activation with the TLR-4 agonist lipopolysaccharide. To validate our in silico data, we challenged DC's with various agonists that recognize all mouse TLRs and assessed expression of a set of immune and inflammatory marker genes. This approach identified a differential contribution of MARCO to TLR activation and validated a major role for MARCO in mounting an inflammatory response. Together, our data demonstrate that MARCO differentially affects TLR-induced DC activation and suggest targeting of MARCO could lead to different outcomes that depend on the inflammatory context encountered by DC.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Adhesion Molecules / metabolism
  • Complement Factor I / metabolism
  • Computer Simulation
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Gene Expression Regulation / immunology
  • Immunity, Innate*
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Lectins, C-Type / metabolism
  • Ligands
  • Lipopolysaccharides / administration & dosage
  • Macrophages / immunology
  • Mice
  • Receptors, Cell Surface / metabolism
  • Receptors, IgG / metabolism
  • Receptors, Immunologic / immunology*
  • Receptors, Immunologic / metabolism
  • Receptors, Scavenger / immunology
  • Toll-Like Receptor 4 / agonists
  • Toll-Like Receptor 4 / immunology*

Substances

  • Cell Adhesion Molecules
  • DC-specific ICAM-3 grabbing nonintegrin
  • Fcgr4 protein, mouse
  • Lectins, C-Type
  • Ligands
  • Lipopolysaccharides
  • Marco protein, mouse
  • Receptors, Cell Surface
  • Receptors, IgG
  • Receptors, Immunologic
  • Receptors, Scavenger
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Complement Factor I

Associated data

  • GEO/GSE55068

Grant support

This work was supported by the Prostate Cancer Foundation Young Investigator Award (M.S. Arredouani) and the Department of Defense Prostate Cancer Research Program New Investigator Award W81XWH-09-1-0448 (M.S. Arredouani). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.