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 a...
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2016
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| Online Access: | http://hdl.handle.net/1721.1/100590 |
| _version_ | 1826192407575658496 |
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| author | Hassan, Musa A. Jensen, Kirk D. Hu, Kenneth Boedec, Erwan Prins, Pjotr Saeij, Jeroen Butty, Vincent L G |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Hassan, Musa A. Jensen, Kirk D. Hu, Kenneth Boedec, Erwan Prins, Pjotr Saeij, Jeroen Butty, Vincent L G |
| author_sort | Hassan, Musa A. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T09:11:52Z |
| format | Article |
| id | mit-1721.1/100590 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:11:52Z |
| publishDate | 2016 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/1005902022-09-26T11:02:02Z Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection Hassan, Musa A. Jensen, Kirk D. Hu, Kenneth Boedec, Erwan Prins, Pjotr Saeij, Jeroen Butty, Vincent L G Massachusetts Institute of Technology. Department of Biology Hassan, Musa A. Jensen, Kirk D. Butty, Vincent Hu, Kenneth Boedec, Erwan Saeij, Jeroen 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 (London, England)-Massachusetts Institute of Technology Postdoctoral Fellowship and Recruitment Enhancement Cancer Research Institute (New York, N.Y.) (Postdoctoral Fellowship) New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (Grant AIO57159) National Institutes of Health (U.S.) (Grant RO1-AI080621) Pew Charitable Trusts 2016-01-04T18:45:26Z 2016-01-04T18:45:26Z 2015-10 2015-03 Article http://purl.org/eprint/type/JournalArticle 1553-7404 http://hdl.handle.net/1721.1/100590 Hassan, Musa A., Kirk D. Jensen, Vincent Butty, Kenneth Hu, Erwan Boedec, Pjotr Prins, and Jeroen P. J. Saeij. “Transcriptional and Linkage Analyses Identify Loci That Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection.” Edited by Barbara E. Stranger. PLOS Genetics 11, no. 10 (October 28, 2015): e1005619. en_US http://dx.doi.org/10.1371/journal.pgen.1005619 PLOS Genetics Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science Public Library of Science |
| spellingShingle | Hassan, Musa A. Jensen, Kirk D. Hu, Kenneth Boedec, Erwan Prins, Pjotr Saeij, Jeroen Butty, Vincent L G Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection |
| title | Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection |
| title_full | Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection |
| title_fullStr | Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection |
| title_full_unstemmed | Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection |
| title_short | Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection |
| title_sort | transcriptional and linkage analyses identify loci that mediate the differential macrophage response to inflammatory stimuli and infection |
| url | http://hdl.handle.net/1721.1/100590 |
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