TY - JOUR
T1 - Network analysis reveals a distinct axis of macrophage activation in response to conflicting inflammatory cues
AU - Liu, Xiaji
AU - Zhang, Jingyuan
AU - Zeigler, Angela C.
AU - Nelson, Anders R.
AU - Lindsey, Merry L.
AU - Saucerman, Jeffrey J.
N1 - Funding Information:
This work was supported by grants from the National Heart, Lung, and Blood Institute (HL075360, HL137755, HL127944, HL129823, and HL137319), grants from the National Institutes of Health (GM104357, GM114833, GM115428, HL051971, HL075360, and HL105324), the Biomedical Laboratory Research and Development Service of the U.S. Department of Veterans Affairs under Award 5I01BX000505, and the National Science Foundation Directorate for Engineering (1252854).
Publisher Copyright:
Copyright © 2021 by The American Association of Immunologists, Inc.
PY - 2021/2/15
Y1 - 2021/2/15
N2 - Macrophages are subject to a wide range of cytokine and pathogen signals in vivo, which contribute to differential activation and modulation of inflammation. Understanding the response to multiple, often-conflicting cues that macrophages experience requires a network perspective. In this study, we integrate data from literature curation and mRNA expression profiles obtained from wild type C57/BL6J mice macrophages to develop a large-scale computational model of the macrophage signaling network. In response to stimulation across all pairs of nine cytokine inputs, the model predicted activation along the classic M1–M2 polarization axis but also a second axis of macrophage activation that distinguishes unstimulated macrophages from a mixed phenotype induced by conflicting cues. Along this second axis, combinations of conflicting stimuli, IL-4 with LPS, IFN-g, IFN-b, or TNF-a, produced mutual inhibition of several signaling pathways, e.g., NF-kB and STAT6, but also mutual activation of the PI3K signaling module. In response to combined IFN-g and IL-4, the model predicted genes whose expression was mutually inhibited, e.g., iNOS or Nos2 and Arg1, or mutually enhanced, e.g., Il4ra and Socs1, validated by independent experimental data. Knockdown simulations further predicted network mechanisms underlying functional cross-talk, such as mutual STAT3/STAT6-mediated enhancement of Il4ra expression. In summary, the computational model predicts that network cross-talk mediates a broadened spectrum of macrophage activation in response to mixed pro- and anti-inflammatory cytokine cues, making it useful for modeling in vivo scenarios.
AB - Macrophages are subject to a wide range of cytokine and pathogen signals in vivo, which contribute to differential activation and modulation of inflammation. Understanding the response to multiple, often-conflicting cues that macrophages experience requires a network perspective. In this study, we integrate data from literature curation and mRNA expression profiles obtained from wild type C57/BL6J mice macrophages to develop a large-scale computational model of the macrophage signaling network. In response to stimulation across all pairs of nine cytokine inputs, the model predicted activation along the classic M1–M2 polarization axis but also a second axis of macrophage activation that distinguishes unstimulated macrophages from a mixed phenotype induced by conflicting cues. Along this second axis, combinations of conflicting stimuli, IL-4 with LPS, IFN-g, IFN-b, or TNF-a, produced mutual inhibition of several signaling pathways, e.g., NF-kB and STAT6, but also mutual activation of the PI3K signaling module. In response to combined IFN-g and IL-4, the model predicted genes whose expression was mutually inhibited, e.g., iNOS or Nos2 and Arg1, or mutually enhanced, e.g., Il4ra and Socs1, validated by independent experimental data. Knockdown simulations further predicted network mechanisms underlying functional cross-talk, such as mutual STAT3/STAT6-mediated enhancement of Il4ra expression. In summary, the computational model predicts that network cross-talk mediates a broadened spectrum of macrophage activation in response to mixed pro- and anti-inflammatory cytokine cues, making it useful for modeling in vivo scenarios.
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U2 - 10.4049/jimmunol.1901444
DO - 10.4049/jimmunol.1901444
M3 - Article
C2 - 33408259
AN - SCOPUS:85100499280
SN - 0022-1767
VL - 206
SP - 883
EP - 891
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -