Six distinct NFκB signaling codons convey discrete information to distinguish stimuli and enable appropriate macrophage responses

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.

Automated summary

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.