Molecular Network Analysis of Endometriosis Reveals a Role for c-Jun-Regulated Macrophage Activation

Michael T. Beste, Nicole Pfäffle-Doyle, Emily A. Prentice, Stephanie Morris, D. A. Lauffenburger, Keith Isaacson, Linda G. Griffith
In: PMC · 2014 · W2165955081
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Network analysis of cytokine profiles in endometriosis identified a consensus inflammatory signature linked to macrophage activation, implicating c-Jun and AP-1 in driving disease progression.

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This study employs molecular network analysis to identify inflammatory signatures in endometriosis patients, moving beyond traditional visual classification schemes. Unsupervised multivariate analysis of cytokine profiles revealed a consensus signature of thirteen elevated cytokines associated with common clinical features, which was not observed in subgroups defined by morphology alone. The research highlights the primacy of peritoneal macrophage infiltration and identifies c-Jun-regulated signaling pathways as critical drivers of this inflammatory network, validated through targeted kinase inhibition. This paper is centrally about endometriosis — specifically investigating the role of c-Jun-regulated macrophage activation in disease progression and potential treatment stratification.

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Abstract

Clinical management of endometriosis is limited by the complex relationship between symptom severity, heterogeneous surgical presentation, and variability in clinical outcomes. As a complement to visual classification schemes, molecular profiles of disease activity may improve risk stratification to better inform treatment decisions and identify new approaches to targeted treatment. We use a network analysis of information flow within and between inflammatory cells to discern consensus behaviors characterizing patient subpopulations. Unsupervised multivariate analysis of cytokine profiles quantified by multiplex immunoassays identified a subset of patients with a shared “consensus signature” of 13 elevated cytokines that was associated with common clinical features of endometriosis, but was not observed among patient subpopulations defined by morphologic presentation alone. Enrichment analysis of consensus markers reinforced the primacy of peritoneal macrophage infiltration and activation, which was demonstrably elevated in ex vivo cultures. Although familiar targets of the nuclear factor κB family emerged among overrepresented transcriptional binding sites for consensus markers, our analysis provides evidence for an unexpected contribution from c-Jun, c-Fos, and AP-1 effectors of mitogen-associated kinase signaling. Their crucial involvement in propagation of macrophage-driven inflammatory networks was confirmed via targeted inhibition of upstream kinases. Collectively, these analyses suggest a clinically relevant inflammatory network that may serve as an objective measure for guiding treatment decisions for endometriosis management, and in the future may provide a mechanistic endpoint for assessing efficacy of new agents aimed at curtailing inflammatory mechanisms that drive disease progression.
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Molecular Network Analysis of Endometriosis Reveals a Role for c-Jun-Regulated Macrophage Activation Name Griffith_Molecular network.pdf Size 788.94 KB Format Adobe PDF Checksum (MD5) 0d4c247c1a754006a0958e554122634f Author(s) • • • • • • Beste, Michael T. Pfaffle-Doyle, Nicole Prentice, Emily A. Lauffenburger, Douglas A. Morris, Stephanie N. Isaacson, Keith B. Griffith, Linda G. Date Issued February 2014 Journal Science Translational Medicine Publisher American Association for the Advancement of Science (AAAS) Citation Beste, M. T., N. Pfaffle-Doyle, E. A. Prentice, S. N. Morris, D. A. Lauffenburger, K. B. Isaacson, and L. G. Griffith. “Molecular Network Analysis of Endometriosis Reveals a Role for c-Jun-Regulated Macrophage Activation.” Science Translational Medicine 6, no. 222 (February 5, 2014): 222ra16–222ra16. Version Author's final manuscript Abstract Clinical management of endometriosis is limited by the complex relationship between symptom severity, heterogeneous surgical presentation, and variability in clinical outcomes. As a complement to visual classification schemes, molecular profiles of disease activity may improve risk stratification to better inform treatment decisions and identify new approaches to targeted treatment. We use a network analysis of information flow within and between inflammatory cells to discern consensus behaviors characterizing patient subpopulations. Unsupervised multivariate analysis of cytokine profiles quantified by multiplex immunoassays identified a subset of patients with a shared “consensus signature” of 13 elevated cytokines that was associated with common clinical features of endometriosis, but was not observed among patient subpopulations defined by morphologic presentation alone. Enrichment analysis of consensus markers reinforced the primacy of peritoneal macrophage infiltration and activation, which was demonstrably elevated in ex vivo cultures. Although familiar targets of the nuclear factor κB family emerged among overrepresented transcriptional binding sites for consensus markers, our analysis provides evidence for an unexpected contribution from c-Jun, c-Fos, and AP-1 effectors of mitogen-associated kinase signaling. Their crucial involvement in propagation of macrophage-driven inflammatory networks was confirmed via targeted inhibition of upstream kinases. Collectively, these analyses suggest a clinically relevant inflammatory network that may serve as an objective measure for guiding treatment decisions for endometriosis management, and in the future may provide a mechanistic endpoint for assessing efficacy of new agents aimed at curtailing inflammatory mechanisms that drive disease progression. MIT Department Massachusetts Institute of Technology. Center for Gynepathology Research Massachusetts Institute of Technology. Department of Biological Engineering Terms of Use Creative Commons Attribution-Noncommercial-Share Alike Persistent DSpace Link DOI of Published Version https://doi.org/10.1126/scitranslmed.3007988

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endometriosis

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