The biology of nematode- and IL4Rα-dependent murine macrophage polarization in vivo as defined by RNA-Seq and targeted lipidomics

Blood. 2012 Dec 13;120(25):e93-e104. doi: 10.1182/blood-2012-07-442640. Epub 2012 Oct 16.

Abstract

Alternatively activated macrophages (AAMϕ) are a major component of the response to helminth infection; however, their functions remain poorly defined. To better understand the helminth-induced AAMϕ phenotype, we performed a systems-level analysis of in vivo derived AAMϕ using an established mouse model. With next-generation RNA sequencing, we characterized the transcriptomes of peritoneal macrophages from BALB/c and IL4Rα(-/-) mice elicited by the nematode Brugia malayi, or via intraperitoneal thioglycollate injection. We defined expression profiles of AAMϕ-associated cytokines, chemokines, and their receptors, providing evidence that AAMϕ contribute toward recruitment and maintenance of eosinophilia. Pathway analysis highlighted complement as a potential AAMϕ-effector function. Up-regulated mitochondrial genes support in vitro evidence associating mitochondrial metabolism with alternative activation. We mapped macrophage transcription start sites, defining over-represented cis-regulatory motifs within AAMϕ-associated promoters. These included the binding site for PPAR transcription factors, which maintain mitochondrial metabolism. Surprisingly PPARγ, implicated in the maintenance of AAMϕ, was down-regulated on infection. PPARδ expression, however, was maintained. To explain how PPAR-mediated transcriptional activation could be maintained, we used lipidomics to quantify AAMϕ-derived eicosanoids, potential PPAR ligands. We identified the PPARδ ligand PGI(2) as the most abundant AAMϕ-derived eicosanoid and propose a PGI(2)-PPARδ axis maintains AAMϕ during B malayi implantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Coagulation
  • Brugia malayi / physiology*
  • Chemokines / genetics
  • Complement System Proteins / genetics
  • Cytokines / genetics
  • Eicosanoids / metabolism
  • Filariasis / parasitology*
  • Gene Deletion
  • Gene Expression Regulation
  • Host-Parasite Interactions*
  • Macrophage Activation
  • Macrophages, Peritoneal / immunology*
  • Macrophages, Peritoneal / metabolism
  • Macrophages, Peritoneal / parasitology*
  • Mice
  • Mice, Inbred BALB C
  • Peroxisome Proliferator-Activated Receptors / genetics
  • Peroxisome Proliferator-Activated Receptors / metabolism
  • RNA / genetics
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology*
  • Receptors, Chemokine / genetics
  • Receptors, Cytokine / genetics
  • Transcriptome

Substances

  • Chemokines
  • Cytokines
  • Eicosanoids
  • Il4ra protein, mouse
  • Peroxisome Proliferator-Activated Receptors
  • Receptors, Cell Surface
  • Receptors, Chemokine
  • Receptors, Cytokine
  • RNA
  • Complement System Proteins