Profibrotic monocyte-derived alveolar macrophages as a biomarker and therapeutic target in systemic sclerosis-associated interstitial lung disease [Northwestern]

Interstitial lung disease (ILD) is present in over 60% of patients with systemic sclerosis (SSc) and is the leading cause of SSc-related deaths. Profibrotic monocyte-derived alveolar macrophages (MoAM) play a causal role in the pathogenesis of pulmonary fibrosis in animal models where their persistence in the niche requires signaling through the Colony Stimulating Factor 1 Receptor (CSF1R). We hypothesized that the presence and proportion of MoAM in bronchoalveolar lavage (BAL) fluid from patients with SSc-ILD may be a biomarker of ILD severity. To test this hypothesis, we performed BAL in 9 prospectively enrolled patients with SSc-ILD on imaging and 13 healthy controls and analyzed the cellular fraction using flow cytometry and single-cell RNA sequencing. Compared to healthy controls, patients with SSc-ILD showed increased abundance of MoAM and interstitial macrophages in BAL fluid that was associated with worse lung function and lung disease on imaging. We identified changes in the MoAM transcriptome as a function of treatment with mycophenolate, an effective therapy for SSc-ILD. Bronchoalveolar lavage (BAL) fluid from 10 patients 5 heathy volunteers was obtained at the bronchoscopy suite of Northwestern Memorial Hospital or Yale New Haven Hospital.l. Single cell RNA-seq libraries were prepared with 10x 3' gene expression kit. Libraries were sequenced on Illumina NovaSeq 6000. Gene expression matrices were generated with 10x Cell Ranger v3.1.0 (exon-only mode) software and reads were mapped to GRCh38.84 reference genome (10x Genomics Cell Ranger Human 1.2.0 GRCh38 reference). *************************************************************** Protected Health Information: fastq files have been omitted. ***************************************************************