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PLoS Genet. 2015 Oct 28;11(10):e1005619. doi: 10.1371/journal.pgen.1005619. eCollection 2015 Oct.

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

Author information

1
Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow, United Kingdom; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
2
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
3
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; School of Biotechnology, University of Strasbourg, Strasbourg, France.
4
Laboratory of Nematology, Wageningen University, Wageningen, The Netherlands.
5
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Department of Pathology, Microbiology & Immunology, University of California, Davis, Davis, California, United States of America.

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.

PMID:
26510153
PMCID:
PMC4625001
DOI:
10.1371/journal.pgen.1005619
[Indexed for MEDLINE]
Free PMC Article

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