A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis.
Systemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology.



We used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast the skin and lung microenvironments and to assess the functional role of the inflammatory and fibrotic genes in each organ. Lastly, we tested the expression of macrophage activation state-associated gene sets for enrichment in skin and lung using a Wilcoxon rank sum test.



We identified a common pathogenic gene expression signature-an immune-fibrotic axis-indicative of pro-fibrotic macrophages (MØs) in multiple tissues (skin, lung, esophagus, and peripheral blood mononuclear cells) affected by SSc. While the co-expression of these genes is common to all tissues, the functional consequences of this upregulation differ by organ. We used this disease-associated signature to query tissue-specific functional genomic networks to identify common and tissue-specific pathologies of SSc and related conditions. In contrast to skin, in the lung-specific functional network we identify a distinct lung-resident MØ signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct MØ alternative activation transcriptional programs in SSc-associated 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.
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, 7400 Remsen, Hanover, NH, 03755, USA.
Jaclyn N
JN
Taroni
Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Casey S
CS
Greene
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, 7400 Remsen, Hanover, NH, 03755, USA.
Viktor
V
Martyanov
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, 7400 Remsen, Hanover, NH, 03755, USA.
Tammara A
TA
Wood
Division of Rheumatology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Romy B
RB
Christmann
Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.
Harrison W
HW
Farber
Division of Rheumatology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.|Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15261, USA.
Robert A
RA
Lafyatis
Division of Medicine, University College London, London, UK.
Christopher P
CP
Denton
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Monique E
ME
Hinchcliff
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA.
Patricia A
PA
Pioli
Department of Neurological Sciences, Larner College of Medicine, University of Vermont, HSRF 426, 149 Beaumont Avenue, Burlington, VT, 05405, USA. john.m.mahoney@uvm.edu.
J Matthew
JM
Mahoney
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, 7400 Remsen, Hanover, NH, 03755, USA. michael.l.whitfield@dartmouth.edu.
Michael L
ML
Whitfield
D001706:Biopsy; D004947:Esophagus / Q000378:metabolism; D005355:Fibrosis; D053263:Gene Regulatory Networks; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D009928:Organ Specificity; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000378:metabolism; D059467:Transcriptome
Functional genomics; Lung disease; Macrophage; Scleroderma; Systemic sclerosis