Profibrotic Monocyte-Derived Alveolar Macrophages Are Associated With Disease Severity in Patients With Systemic Sclerosis-Associated Interstitial Lung Disease

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Abstract Rationale: Interstitial lung disease (ILD) affects 40-75% of patients with systemic sclerosis (SSc) and is the leading cause of death in this population. Profibrotic monocyte-derived alveolar macrophages (MoAM)—expressing SPP1, MMP9, CHIT1, CHI3L1—play a causal role in the pathogenesis of pulmonary fibrosis in animal models. In humans, these profibrotic MoAM have been identified in explanted lung tissue from patients with fibrotic ILD yet are absent in healthy donor lung. We aimed to determine the localization of profibrotic MoAM in lung explants from patients with SSc-ILD and hypothesized that the abundance and phenotype of these MoAM are associated with disease severity. Methods: Explants from patients with SSc-ILD were profiled with the Xenium spatial transcriptomic assay. Nine subjects with SSc-ILD and thirteen healthy, non-SSc controls were recruited from three academic centers. Clinical, spirometric, and radiologic characteristics were assessed. Subjects underwent flexible fiberoptic bronchoscopy with bronchoalveolar lavage (BAL). Cell populations from BAL fluid (BALF) were analyzed by single cell RNA sequencing. Their proportional prevalence and transcriptional profiles were tested for association with lung function and extent of pulmonary fibrosis on computed tomography (CT) as quantified by a thoracic radiologist using the Kazerooni score. Results: Single-cell spatial transcriptomic analysis of explanted lung tissue from patients with SSc-ILD demonstrated that profibrotic MoAM were exclusively localized to the airspace. Compared to controls, subjects with SSc-ILD had increased proportions of profibrotic MoAM in BALF (Figure 1A, 1B). The abundance of these MoAM inversely correlated with lung function (Figure 1C) and directly correlated with the extent of fibrosis on CT (Figure 1D). We additionally identified genes across all alveolar macrophage subtypes whose expression significantly correlated with lung function. Differential expression analysis revealed significant transcriptomic changes in tissue-resident alveolar macrophages, MoAM, and subsets of T cells (CD8+ tissue-resident memory, CD4+ effector memory) in subjects with SSc-ILD compared to controls. Furthermore, we identified a transcriptomic signature in BALF from subjects with SSc-ILD that was associated with treatment with mycophenolate mofetil and a reduction in interferon gamma levels. Conclusions: Profibrotic MoAM are localized to the airspace of patients with SSc-ILD and can be sampled by BAL. Abundance of these MoAM and gene expression profiles are associated with functional and radiologic severity of disease. Our data suggest that profibrotic MoAM may serve as a biomarker of SSc-ILD and a potential target for therapy.

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