A Novel Multi-network Approach Reveals Tissue-specific Cellular Modulators of Fibrosis in Systemic Sclerosis, Pulmonary Fibrosis and Pulmonary Arterial Hypertension

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.