Background/Purpose: Systemic sclerosis (SSc) is characterized by multi-organ involvement and clinical heterogeneity. “Big data” approaches have yielded powerful tools to infer tissue-specific pathobiology. Large amounts of SSc gene expression data have been generated from different tissues and patient samples with distinct SSc clinical pathology. We performed an integrative meta-analysis of ten different SSc gene expression datasets that identified common disease drivers and tissue-specific distinctions in macrophage (MØ) phenotypes.

Methods: We developed and employed a novel data mining procedure that identified conserved coexpression patterns between ten datasets from four different tissues (skin, lung, esophagus, blood) with multiple clinical manifestations (pulmonary arterial hypertension [PAH], PF, limited and diffuse subtypes). We identified genes and processes that were conserved across all solid tissues and were highly expressed in pulmonary manifestations of SSc. We used these modules to query tissue-specific gene-gene interaction networks and analyzed the resulting lung- and skin-specific networks to infer common and tissue-specific fibrotic and inflammatory pathways.

Results: We identified a common gene signature indicative of an immune fibrotic process (IFP) composed of alternatively activated MØs that contribute to the extracellular matrix (ECM) remodeling processes. This signature was found in PAH and PF in lung, as well as the inflammatory molecular subsets in skin and esophagus. Analysis of the tissue-specific networks revealed a coupling of inflammatory and ECM processes in solid tissues that was absent in PBMC samples. We then rigorously contrasted the lung- and skin-specific gene interaction networks to identify a distinct lung resident MØ signature (LR-MØ) associated with lipid stimulation and alternative activation. Distinct MØ alternative activation transcriptional programs were observed in SSc-PF lung and SSc inflammatory skin.

Conclusion: We find evidence for alternatively activated MØs in multiple SSc tissues. However, there are subtle differences in the MØ transcriptional programs detected in skin and lung uncovered through multi-network systems analyses. In particular, different microenvironments likely provide distinct stimuli to infiltrating MØs that determine the pro-fibrotic character of these cells. This work suggests that the plasticity of this lineage is central to the divergence of fibrotic processes in multiple SSc-affected tissues and is a central component of an immune-fibrotic process driving disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-multi-network-approach-reveals-tissue-specific-cellular-modulators-of-fibrosis-in-systemic-sclerosis-pulmonary-fibrosis-and-pulmonary-arterial-hypertension/