Identification and Physiological Significance of Temporal Nfκb Signaling Codewords Deployed by Macrophages to Classify Immune Threats

Abstract

Inflammatory pathologies often involve dysregulated macrophage functions. In health, macrophages are immune sentinels that initiate inflammatory responses via the transcription factor NFkB. The temporal pattern of NFkB activity determines which genes are expressed, but how such temporal signaling code works in primary immune cells remains unexplored. For this study, we developed tools to enable high-throughput analysis of live, primary macrophages responding to host- and pathogen-derived stimuli. An information-theoretic workflow identified six dynamical features that constitute codewords that convey stimulus information to the nucleus. In particular, oscillatory trajectories are a hallmark of the responses to host cytokine TNF. Remarkably, examining macrophages derived from a systemic autoimmune disease model suggests that confusion of two NFkB signaling codewords, and thus miscoding of TNF as a pathogen-derived stimulus, may underlie sporadic inflammatory pathology. Overall, this study identifies six codewords of the temporal NFkB signaling code for classifying immune threats and demonstrates their biological significance.