Identification and validation of ifit1 as an important innate immune bottleneck

Jason E. McDermott, Keri B. Vartanian, Hugh Mitchell, Susan L. Stevens, Antonio Sanfilippo, Mary P. Stenzel-Poore

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The innate immune system plays important roles in a number of disparate processes. Foremost, innate immunity is a first responder to invasion by pathogens and triggers early defensive responses and recruits the adaptive immune system. The innate immune system also responds to endogenous damage signals that arise from tissue injury. Recently it has been found that innate immunity plays an important role in neuroprotection against ischemic stroke through the activation of the primary innate immune receptors, Toll-like receptors (TLRs). Using several large-scale transcriptomic data sets from mouse and mouse macrophage studies we identified targets predicted to be important in controlling innate immune processes initiated by TLR activation. Targets were identified as genes with high betweenness centrality, so-called bottlenecks, in networks inferred from statistical associations between gene expression patterns. A small set of putative bottlenecks were identified in each of the data sets investigated including interferon-stimulated genes (Ifit1, Ifi47, Tgtp and Oasl2) as well as genes uncharacterized in immune responses (Axud1 and Ppp1r15a). We further validated one of these targets, Ifit1, in mouse macrophages by showing that silencing it suppresses induction of predicted downstream genes by lipopolysaccharide (LPS)-mediated TLR4 activation through an unknown direct or indirect mechanism. Our study demonstrates the utility of network analysis for identification of interesting targets related to innate immune function, and highlights that Ifit1 can exert a positive regulatory effect on downstream genes.

Original languageEnglish
Article numbere36465
JournalPLoS One
Volume7
Issue number6
DOIs
Publication statusPublished - 20 Jun 2012
Externally publishedYes

Fingerprint

Genes
Immune system
Immune System
Macrophages
Toll-Like Receptors
Chemical activation
genes
Innate Immunity
mice
macrophages
Pathogens
interferons
Electric network analysis
transcriptomics
stroke
Gene expression
Interferons
lipopolysaccharides
Lipopolysaccharides
Stroke

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

McDermott, J. E., Vartanian, K. B., Mitchell, H., Stevens, S. L., Sanfilippo, A., & Stenzel-Poore, M. P. (2012). Identification and validation of ifit1 as an important innate immune bottleneck. PLoS One, 7(6), [e36465]. https://doi.org/10.1371/journal.pone.0036465

Identification and validation of ifit1 as an important innate immune bottleneck. / McDermott, Jason E.; Vartanian, Keri B.; Mitchell, Hugh; Stevens, Susan L.; Sanfilippo, Antonio; Stenzel-Poore, Mary P.

In: PLoS One, Vol. 7, No. 6, e36465, 20.06.2012.

Research output: Contribution to journalArticle

McDermott, JE, Vartanian, KB, Mitchell, H, Stevens, SL, Sanfilippo, A & Stenzel-Poore, MP 2012, 'Identification and validation of ifit1 as an important innate immune bottleneck', PLoS One, vol. 7, no. 6, e36465. https://doi.org/10.1371/journal.pone.0036465
McDermott JE, Vartanian KB, Mitchell H, Stevens SL, Sanfilippo A, Stenzel-Poore MP. Identification and validation of ifit1 as an important innate immune bottleneck. PLoS One. 2012 Jun 20;7(6). e36465. https://doi.org/10.1371/journal.pone.0036465
McDermott, Jason E. ; Vartanian, Keri B. ; Mitchell, Hugh ; Stevens, Susan L. ; Sanfilippo, Antonio ; Stenzel-Poore, Mary P. / Identification and validation of ifit1 as an important innate immune bottleneck. In: PLoS One. 2012 ; Vol. 7, No. 6.
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