Transcriptional and linkage analyses identify loci that mediate the differential macrophage response to inflammatory stimuli and infection

Hassan, M. A., Jensen, K. D., Butty, V., Hu, K., Boedec, E., Prins, P. and Saeij, J. P. J. (2015) Transcriptional and linkage analyses identify loci that mediate the differential macrophage response to inflammatory stimuli and infection. PLoS Genetics, 11(10), e1005619. (doi:10.1371/journal.pgen.1005619) (PMID:26510153) (PMCID:PMC4625001)

[img]
Preview
Text
111680.pdf - Published Version
Available under License Creative Commons Attribution.

1MB

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hassan, Dr Musa
Authors: Hassan, M. A., Jensen, K. D., Butty, V., Hu, K., Boedec, E., Prins, P., and Saeij, J. P. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Genetics
Publisher:Public Library of Science
ISSN:1553-7390
ISSN (Online):1553-7404
Copyright Holders:Copyright © 2015 Hassan et al.
First Published:First published in PLoS Genetics 11(10):e1005619
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record