Journal
IMMUNITY
Volume 54, Issue 5, Pages 916-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2021.04.011
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Funding
- NIH [R01GM117134, R01AI127864, T32GM008042, T32HL69766, T32GM008185]
- NIH NRSA Predoctoral Fellowship [F31AI138450]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [419234150]
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The dynamics of NF kappa B signaling can classify immune threats through six signaling codons, and confusion of these codons may underlie the etiology of some inflammatory diseases.NF kappa B activity determines the type of gene expression and response in macrophages. An oscillatory trajectory is a hallmark of responses to cytokine stimuli.
Macrophages initiate inflammatory responses via the transcription factor NF kappa B. The temporal pattern of NF kappa B activity determines which genes are expressed and thus, the type of response that ensues. Here, we examined how information about the stimulus is encoded in the dynamics of NF kappa B activity. We generated an mVenus-RelA reporter mouse line to enable high-throughput live-cell analysis of primary macrophages responding to host- and pathogen-derived stimuli. An information-theoretic workflow identified six dynamical features-termed signaling codons-that convey stimulus information to the nucleus. In particular, oscillatory trajectories were a hallmark of responses to cytokine but not pathogen-derived stimuli. Single-cell imaging and RNA sequencing of macrophages from a mouse model of Sjogren's syndrome revealed inappropriate responses to stimuli, suggestive of confusion of two NF kappa B signaling codons. Thus, the dynamics of NF kappa B signaling classify immune threats through six signaling codons, and signal confusion based on defective codon deployment may underlie the etiology of some inflammatory diseases.
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