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Identification and physiological significance of temporal NFκB signaling codewords deployed by macrophages to classify immune threats

Brooks Taylor, Adewunmi Adelaja, Yi Liu, Stefanie Luecke, View ORCID ProfileAlexander Hoffmann
doi: https://doi.org/10.1101/2020.05.23.112862
Brooks Taylor
Institute for Quantitative and Computational Biosciences (QCBio), Molecular Biology Institute (MBI), and Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California, Los Angeles (UCLA), 611 Charles E. Young Dr S, Los Angeles, CA 90093.
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Adewunmi Adelaja
Institute for Quantitative and Computational Biosciences (QCBio), Molecular Biology Institute (MBI), and Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California, Los Angeles (UCLA), 611 Charles E. Young Dr S, Los Angeles, CA 90093.
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Yi Liu
Institute for Quantitative and Computational Biosciences (QCBio), Molecular Biology Institute (MBI), and Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California, Los Angeles (UCLA), 611 Charles E. Young Dr S, Los Angeles, CA 90093.
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Stefanie Luecke
Institute for Quantitative and Computational Biosciences (QCBio), Molecular Biology Institute (MBI), and Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California, Los Angeles (UCLA), 611 Charles E. Young Dr S, Los Angeles, CA 90093.
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Alexander Hoffmann
Institute for Quantitative and Computational Biosciences (QCBio), Molecular Biology Institute (MBI), and Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California, Los Angeles (UCLA), 611 Charles E. Young Dr S, Los Angeles, CA 90093.
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  • ORCID record for Alexander Hoffmann
  • For correspondence: ahoffmann@ucla.edu
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Abstract

Acute and chronic inflammatory pathologies involve misregulation of macrophage functions. Physiologically, macrophages are immune sentinels that initiate inflammatory responses via the transcription factor NFκB. The temporal pattern of NFκB activity determines which genes are expressed, suggesting that a temporal signaling code specifies a stimulus-appropriate immune response. To identify the signaling codewords, 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 NFκB 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 NFκB signaling code for classifying immune threats and demonstrates their biological significance.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://data.mendeley.com/datasets/6wksmvh5p4/draft?a=832656ba-2bde-40a4-8bbc-4cecb1d9543d

  • https://github.com/brookstaylorjr/MACKtrack

  • https://github.com/Adewunmi91/nfkb_model

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 26, 2020.
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Identification and physiological significance of temporal NFκB signaling codewords deployed by macrophages to classify immune threats
Brooks Taylor, Adewunmi Adelaja, Yi Liu, Stefanie Luecke, Alexander Hoffmann
bioRxiv 2020.05.23.112862; doi: https://doi.org/10.1101/2020.05.23.112862
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Identification and physiological significance of temporal NFκB signaling codewords deployed by macrophages to classify immune threats
Brooks Taylor, Adewunmi Adelaja, Yi Liu, Stefanie Luecke, Alexander Hoffmann
bioRxiv 2020.05.23.112862; doi: https://doi.org/10.1101/2020.05.23.112862

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