Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection.
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.
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.
Musa A
MA
Hassan
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Kirk D
KD
Jensen
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Vincent
V
Butty
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Kenneth
K
Hu
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; School of Biotechnology, University of Strasbourg, Strasbourg, France.
Erwan
E
Boedec
Laboratory of Nematology, Wageningen University, Wageningen, The Netherlands.
Pjotr
P
Prins
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.
Jeroen P J
JP
Saeij
D000818:Animals; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D056726:Genetic Association Studies; D008040:Genetic Linkage; D007249:Inflammation / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D007371:Interferon-gamma / Q000008:administration & dosage / Q000235:genetics; D008262:Macrophage Activation / Q000235:genetics*; D008264:Macrophages / Q000382:microbiology / Q000473:pathology; D051379:Mice; D014122:Toxoplasma / Q000472:pathogenicity; D014123:Toxoplasmosis / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000235:genetics
D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C541494:DDX1 protein, mouse; D053487:DEAD-box RNA Helicases