Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection

Musa A. Hassan, Kirk D. Jensen, Vincent Butty, Kenneth Hu, Erwan Boedec, Pjotr Prins, Jeroen Saeij

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Macrophages display flexible activation states that range between pro-inflammatory (classical activation) and anti-inflammatory (alternative activation). These macrophage polarization states contribute to a variety of organismal phenotypes such as tissue remodeling and susceptibility to infectious and inflammatory diseases. Several macrophage- or immune-related genes have been shown to modulate infectious and inflammatory disease pathogenesis. However, the potential role that differences in macrophage activation phenotypes play in modulating differences in susceptibility to infectious and inflammatory disease is just emerging. We integrated transcriptional profiling and linkage analyses to determine the genetic basis for the differential murine macrophage response to inflammatory stimuli and to infection with the obligate intracellular parasite Toxoplasma gondii. We show that specific transcriptional programs, defined by distinct genomic loci, modulate macrophage activation phenotypes. In addition, we show that the difference between AJ and C57BL/6J macrophages in controlling Toxoplasma growth after stimulation with interferon gamma and tumor necrosis factor alpha mapped to chromosome 3, proximal to the Guanylate binding protein (Gbp) locus that is known to modulate the murine macrophage response to Toxoplasma. Using an shRNA-knockdown strategy, we show that the transcript levels of an RNA helicase, Ddx1, regulates strain differences in the amount of nitric oxide produced by macrophage after stimulation with interferon gamma and tumor necrosis factor. Our results provide a template for discovering candidate genes that modulate macrophage-mediated complex traits.

Original languageEnglish (US)
Article numbere1005619
JournalPLoS Genetics
Volume11
Issue number10
DOIs
StatePublished - 2015

Fingerprint

linkage (genetics)
phenotype
macrophages
Macrophages
tumor
loci
Infection
infection
Toxoplasma
gene
nitric oxide
Communicable Diseases
macrophage activation
Macrophage Activation
RNA
chromosome
genomics
parasite
polarization
interferon-gamma

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection. / Hassan, Musa A.; Jensen, Kirk D.; Butty, Vincent; Hu, Kenneth; Boedec, Erwan; Prins, Pjotr; Saeij, Jeroen.

In: PLoS Genetics, Vol. 11, No. 10, e1005619, 2015.

Research output: Contribution to journalArticle

Hassan, Musa A. ; Jensen, Kirk D. ; Butty, Vincent ; Hu, Kenneth ; Boedec, Erwan ; Prins, Pjotr ; Saeij, Jeroen. / Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection. In: PLoS Genetics. 2015 ; Vol. 11, No. 10.
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