Changes in macrophage transcriptome associate with systemic sclerosis and mediate contribution to disease risk.
Aida Moreno-Moral, Marta Bagnati, Surya Koturan, Jeong-Hun Ko, Carmen Fonseca, Nathan Harmston, Laurence Game, Javier Martin, Voon Ong, David J Abraham, Christopher P Denton, Jacques Behmoaras, Enrico Petretto
Author Information
Aida Moreno-Moral: Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore.
Marta Bagnati: Centre for Complement and Inflammation Research, Hammersmith Hospital, Imperial College London, London, UK.
Surya Koturan: Centre for Complement and Inflammation Research, Hammersmith Hospital, Imperial College London, London, UK.
Jeong-Hun Ko: Centre for Complement and Inflammation Research, Hammersmith Hospital, Imperial College London, London, UK.
Carmen Fonseca: Division of Medicine, Department of Inflammation, Centre for Rheumatology and Connective Tissue Diseases, Royal Free and University College Medical School, University College London, London, UK.
Nathan Harmston: Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore.
Laurence Game: Genomics Laboratory, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
Javier Martin: Instituto de Parasitología y Biomedicina López Neyra, Consejo Superior de Investigaciones Cientıficas, Granada, Spain.
Voon Ong: Division of Medicine, Department of Inflammation, Centre for Rheumatology and Connective Tissue Diseases, Royal Free and University College Medical School, University College London, London, UK.
David J Abraham: Division of Medicine, Department of Inflammation, Centre for Rheumatology and Connective Tissue Diseases, Royal Free and University College Medical School, University College London, London, UK.
Christopher P Denton: Division of Medicine, Department of Inflammation, Centre for Rheumatology and Connective Tissue Diseases, Royal Free and University College Medical School, University College London, London, UK.
Jacques Behmoaras: Centre for Complement and Inflammation Research, Hammersmith Hospital, Imperial College London, London, UK.
Enrico Petretto: Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore.
OBJECTIVES: Several common and rare risk variants have been reported for systemic sclerosis (SSc), but the effector cell(s) mediating the function of these genetic variants remains to be elucidated. While innate immune cells have been proposed as the critical targets to interfere with the disease process underlying SSc, no studies have comprehensively established their effector role. Here we investigated the contribution of monocyte-derived macrophages (MDMs) in mediating genetic susceptibility to SSc. METHODS: We carried out RNA sequencing and genome-wide genotyping in MDMs from 57 patients with SSc and 15 controls. Our differential expression and expression quantitative trait locus (eQTL) analysis in SSc was further integrated with epigenetic, expression and eQTL data from skin, monocytes, neutrophils and lymphocytes. RESULTS: We identified 602 genes upregulated and downregulated in SSc macrophages that were significantly enriched for genes previously implicated in SSc susceptibility (P=5×10), and 270 -regulated genes in MDMs. Among these, was reported to carry an SSc risk variant (rs3894194) regulating expression of neighbouring genes in blood. We show that is upregulated in SSc MDMs (P=8.4×10) but not in the skin, and is a significant eQTL in SSc macrophages and lipopolysaccharide/interferon gamma (IFNγ)-stimulated monocytes. Furthermore, we identify an SSc macrophage transcriptome signature characterised by upregulation of glycolysis, hypoxia and mTOR signalling and a downregulation of IFNγ response pathways. CONCLUSIONS: Our data further establish the link between macrophages and SSc, and suggest that the contribution of the rs3894194 risk variant to SSc susceptibility can be mediated by expression in macrophages.
