Macrophage heterogeneity and interferon signaling in systemic sclerosis

A type I interferon (IFN) signature is detectable in the blood and lesional tissue of a large proportion of systemic sclerosis (SSc) patients and is increasingly recognized as an early and pathogenic feature of SSc. Although plasmacytoid dendritic cells (pDCs) were long regarded as the principal source of IFNs, recent evidence has increasingly implicated monocytes/macrophages as key contributors. The purpose of this review is summarizing evidence of macrophage-specific IFN axis in SSc, which produce and respond to IFN at the interface of inflammation followed by fibrosis in SSc pathogenesis.

Macrophages play a central role in abnormal type I IFN signaling contributing to profibrotic activity. Recent studies have identified distinct SSc-associated macrophage subsets and signaling pathways that actively drive fibrosis. Emerging macrophage-focused therapies show promise for reducing fibrosis, particularly in biologically defined patient subgroups.

We summarize the IFN signaling pathways that operate within macrophages, the genetic and metabolic factors that sustain IFN production, the cellular crosstalk that translates macrophage IFN signals into matrix deposition, and the emerging therapeutic strategies that aim to interrupt this axis in SSc.