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Cell Syst. 2017 Jul 26;5(1):25-37.e3. doi: 10.1016/j.cels.2017.06.014.

Systematic Investigation of Multi-TLR Sensing Identifies Regulators of Sustained Gene Activation in Macrophages.

Author information

1
Signaling Systems Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
2
Bioinformatics Group, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
3
Signaling Systems Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: fraseri@niaid.nih.gov.

Abstract

A typical pathogen presents a combination of Toll-like receptor (TLR) ligands during infection. Although individual TLR pathways have been well characterized, the nature of this "combinatorial code" in pathogen sensing remains unclear. Here, we conducted a comprehensive transcriptomic analysis of primary macrophages stimulated with all possible pairwise combinations of four different TLR ligands to understand the requirements, kinetics, and outcome of combined pathway engagement. We find that signal integration between TLR pathways leads to non-additive responses for a subset of immune mediators with sustained expression (>6 hr) properties and T cell polarizing function. To identify the underlying regulators, we conducted a focused RNAi screen and identified four genes-Helz2, Phf11d, Sertad3, and Zscan12-which preferentially affect the late phase response of TLR-induced immune effector expression. This study reveals key molecular details of how contemporaneous signaling through multiple TLRs, as would often be the case with pathogen infection, produce biological outcomes distinct from the single ligands typically used to characterize TLR pathways.

KEYWORDS:

Toll-like receptors; bacterial infection; innate immunity; signaling pathway crosstalk; transcriptional regulation

PMID:
28750197
PMCID:
PMC5584636
DOI:
10.1016/j.cels.2017.06.014
[Indexed for MEDLINE]
Free PMC Article

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