RT Journal Article
SR Electronic
T1 A Novel Multi-network Approach Reveals Tissue-specific Cellular Modulators of Fibrosis in Systemic Sclerosis, Pulmonary Fibrosis and Pulmonary Arterial Hypertension
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 038950
DO 10.1101/038950
A1 Jaclyn N Taroni
A1 Casey S Greene
A1 Viktor Martyanov
A1 Tammara A Wood
A1 Romy Christmann
A1 Harrison W Farber
A1 Robert A Lafyatis
A1 Christopher P Denton
A1 Monique E Hinchcliff
A1 Patricia A Pioli
A1 J. Matthew Mahoney
A1 Michael L Whitfield
YR 2016
UL http://biorxiv.org/content/early/2016/07/07/038950.abstract
AB We have used integrative genomics to determine if a common molecular mechanism underlies different clinical manifestations in systemic sclerosis (SSc), and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH). We identified a common pathogenic gene expression signature - an immune-fibrotic axis-indicative of pro-fibrotic macrophages in multiple affected tissues (skin, lung, esophagus and PBMCs) of SSc, PF, and PAH. We used this disease-associated signature to query tissue-specific functional genomic networks. This allowed us to identify common and tissue-specific pathology of SSc and related conditions. We rigorously contrasted the lung- and skin-specific gene-gene interaction networks to identify a distinct lung resident macrophage signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct macrophages alternative activation transcriptional programs in SSc-PF lung and in the skin of patients with an "inflammatory" SSc gene expression signature. Our results suggest that the innate immune system is central to SSc disease processes, but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases.