TY - JOUR
T1 - Experimentally-derived fibroblast gene signatures identify molecular pathways associated with distinct subsets of systemic sclerosis patients in three independent cohorts
AU - Johnson, Michael E.
AU - Mahoney, J. Matthew
AU - Taroni, Jaclyn
AU - Sargent, Jennifer L.
AU - Marmarelis, Eleni
AU - Wu, Ming Ru
AU - Varga, John
AU - Hinchcliff, Monique E.
AU - Whitfield, Michael L.
N1 - Funding Information:
This work was supported by the Scleroderma Research Foundation (SRF) (MLW, MH), P50AR060780 (MLW), P30AR061271 (MLW) and U01AR055063 (MLW and R. Lafyatis). JMM was supported by Award Number R25 CA134286-01 from the National Cancer Institute (NCI). JT was supported by Award Number T32GM008704 from the National Institute of General Medical Sciences (NIGMS). MEJ was also supported by a SYNERGY Grant from the Geisel School of Medicine at Dartmouth (to MLW). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIGMS, NIAMS, NCI or the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. MEJ would like to thank members of the Whitfield lab for helpful discussions.
Publisher Copyright:
© 2015 Johnson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - Genome-wide expression profiling in systemic sclerosis (SSc) has identified four 'intrinsic' subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which shows deregulation of distinct signaling pathways; however, the full set of pathways contributing to this differential gene expression has not been fully elucidated. Here we examine experimentally derived gene expression signatures in dermal fibroblasts for thirteen different signaling pathways implicated in SSc pathogenesis. These data show distinct and overlapping sets of genes induced by each pathway, allowing for a better understanding of the molecular relationship between profibrotic and immune signaling networks. Pathway-specific gene signatures were analyzed across a compendium of microarray datasets consisting of skin biopsies from three independent cohorts representing 80 SSc patients, 4 morphea, and 26 controls. IFNα signaling showed a strong association with early disease, while TGFβ signaling spanned the fibroproliferative and inflammatory subsets, was associated with worse MRSS, and was higher in lesional than non-lesional skin. The fibroproliferative subset was most strongly associated with PDGF signaling, while the inflammatory subset demonstrated strong activation of innate immune pathways including TLR signaling upstream of NF-κB. The limited and normal-like subsets did not show associations with fibrotic and inflammatory mediators such as TGFβ and TNFα. The normal-like subset showed high expression of genes associated with lipid signaling, which was absent in the inflammatory and limited subsets. Together, these data suggest a model by which IFNα is involved in early disease pathology, and disease severity is associated with active TGFβ signaling.
AB - Genome-wide expression profiling in systemic sclerosis (SSc) has identified four 'intrinsic' subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which shows deregulation of distinct signaling pathways; however, the full set of pathways contributing to this differential gene expression has not been fully elucidated. Here we examine experimentally derived gene expression signatures in dermal fibroblasts for thirteen different signaling pathways implicated in SSc pathogenesis. These data show distinct and overlapping sets of genes induced by each pathway, allowing for a better understanding of the molecular relationship between profibrotic and immune signaling networks. Pathway-specific gene signatures were analyzed across a compendium of microarray datasets consisting of skin biopsies from three independent cohorts representing 80 SSc patients, 4 morphea, and 26 controls. IFNα signaling showed a strong association with early disease, while TGFβ signaling spanned the fibroproliferative and inflammatory subsets, was associated with worse MRSS, and was higher in lesional than non-lesional skin. The fibroproliferative subset was most strongly associated with PDGF signaling, while the inflammatory subset demonstrated strong activation of innate immune pathways including TLR signaling upstream of NF-κB. The limited and normal-like subsets did not show associations with fibrotic and inflammatory mediators such as TGFβ and TNFα. The normal-like subset showed high expression of genes associated with lipid signaling, which was absent in the inflammatory and limited subsets. Together, these data suggest a model by which IFNα is involved in early disease pathology, and disease severity is associated with active TGFβ signaling.
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U2 - 10.1371/journal.pone.0114017
DO - 10.1371/journal.pone.0114017
M3 - Article
C2 - 25607805
AN - SCOPUS:84935081357
SN - 1932-6203
VL - 10
JO - PLoS One
JF - PLoS One
IS - 1
M1 - e0114017
ER -