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Monocyte and Macrophage Transcriptional Phenotypes in Systemic Juvenile Idiopathic Arthritis Reveal TRIM8 as a Mediator of IFN-γ Hyper-responsiveness and Risk for Macrophage Activation Syndrome

ABSTRACT: Systemic juvenile idiopathic arthritis (SJIA) confers high risk for macrophage activation syndrome (MAS), a life-threatening episode of hyperinflammation driven by IFN-γ. Monocytes in SJIA display IFN-γhyperresponsiveness, but the molecular basis of this remains unclear. The objective of this study is to identify monocyte and macrophage polarization phenotypes including features of interferon response. Bulk RNA-seq of purified SJIA monocytes revealed marked transcriptional changes in patients with elevated ferritin levels. We identified substantial overlap with multiple polarization states but little evidence of IFN-induced signature. Interestingly, among the most highly upregulated genes was tripartite motif containing 8 (TRIM8), a positive regulator of IFN-γ signaling. Single cell RNA-seq of bone marrow macrophages (BMM) from a patient with SJIA and early MAS identified a distinct subpopulation of BMM with altered transcriptomes consistent with hemophagocytes, including upregulated IFN-γ response pathways. These BMM also showed significantly increased expression of TRIM8. In vitro knock-down of TRIM8 in macrophages caused significant reductions in IFN-γ responsiveness. In conclusions, we identify a clear IFN-γ response phenotype in BMM during MAS. TRIM8 is upregulated in both monocytes and macrophages in SJIA, and required for macrophage IFN-γ response in vitro, providing a molecular mechanism and novel therapeutic for monocyte hyperresponsiveness to IFN-.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147795 | GEO | 2021/02/02

REPOSITORIES: GEO

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