Research Article: Monocyte-driven IFN and TNF programs orchestrate inflammatory networks in antisynthetase syndrome-associated interstitial lung disease
Abstract:
Antisynthetase syndrome-associated interstitial lung disease (ASS-ILD) exhibits clinical heterogeneity and progression, with unclear immunopathogenic mechanisms. This study aimed to define the cell type-specific interferon immune signatures and transcriptional networks underlying ASS-ILD.
Single-cell RNA sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) from three treatment-naive ASS-ILD patients and three healthy controls (67,421 cells). A comprehensive analysis was conducted in conjunction with an external cohort, encompassing 126,026 cells. The analytical pipelines included the following: AUCell for interferon-stimulated gene (ISG) activity scoring, Seurat for clustering, Monocle for trajectory inference, and CellChat for cell–cell communication. The inference of transcription factor activity was facilitated using decoupleR software.
Monocyte-specific ISG activity was identified and validated in an integrated cohort of 126,026 cells. Among the six monocyte subsets, mono2 exhibited elevated IFNG expressions and a preferential inflammatory trajectory, marked by upregulated innate and adaptive immune pathways. Cell-cell interaction modeling revealed dysregulated type II interferon (IFN-II) and tumor necrosis factor (TNF) signaling, with mono2, NK, and CD8 + T cells as key signal transmitters. Regulatory network analysis revealed that the transcription factors ETV5 , IRF5 , IRF7 , RORB , RORC , and SMAD1 drive inflammatory and profibrotic signatures via the IL-17, JAK-STAT, and TGF-? pathways.
This study identifies monocytes as central orchestrators of immune dysregulation in ASS-ILD, highlighting IFN/TNF signaling and associated transcriptional regulators as therapeutic targets.
Introduction:
Antisynthetase syndrome (ASS) is a clinically heterogeneous subset of idiopathic inflammatory myopathies (IIMs), defined by the presence of myositis-specific autoantibodies (MSAs) targeting aminoacyl-tRNA synthetases, including Jo-1, EJ, OJ, PL-7, PL-12, KS, Hs, and Zo ( 1 ). ASS typically presents with a triad of inflammatory myopathy, arthritis, and interstitial lung disease (ILD), though phenotypic variability is considerable ( 2 ). Among these manifestations, pulmonary involvement is both the most frequent and…
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