Biology subjects

Reyfman, P. A.

Publications and source records attributed to Reyfman, P. A..

6 recordsLinked to original sources

bioRxiv2025

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

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 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 analyzed BAL fluid from 9 prospectively enrolled patients with SSc-ILD and 13 healthy controls using flow cytometry and single-cell RNA sequencing. Patients with SSc-ILD had more MoAM and interstitial macrophages in BAL fluid than healthy controls, and their abundance was associated with lung fibrosis severity. We identified changes in the MoAM transcriptome as a function of treatment with mycophenolate, an effective therapy for SSc-ILD. In SSc-ILD lung explants, spatial transcriptomics identified an expanded population of interstitial macrophages spilling into the alveolar space. Our findings suggest that the proportion of profibrotic MoAM and interstitial macrophages in BAL fluid may serve as a biomarker of SSc-ILD and credential them as possible targets for therapy.

immunology↗

bioRxiv2020

Influenza-induced activation of recruited alveolar macrophages during the early inflammatory phase drives lung injury and lethality

Severe respiratory virus infections initiate a robust host immune response that contributes to disease severity. Immunomodulatory strategies that limit virus-initiated inflammation are of critical importance. In this study, we compared the host response to influenza A virus (IAV) infection in susceptible animals (wild-type, WT) to resilient mice (Vimentin-/- mice). We identified distinct gene expression patterns in recruited monocyte-derived alveolar macrophages (MoAMs) associated with three phases (Infiltrating, Early Inflammatory, Late Inflammatory) that evolve in sequence over the course of IAV infection. We report a core set of pro-inflammatory genes involved in the WT MoAM Early Inflammatory response that is suppressed in Vim-/- MoAMs. Moreover, we identify CEBPB, Jun-AP1, and IRF transcriptions factors as regulators of this attenuated inflammatory response. We performed causal experiments using bone-marrow chimeras to credential that Vim-/- MoAMs with suppressed pro-inflammatory genes confer protection from influenza-induced mortality in WT susceptible mice. Taken together, these data support the notion that vimentin plays a causal role in determining the pro-inflammatory function of recruited MoAMs and drives IAV-induced lung injury.

immunology↗

bioRxiv2020

Resetting proteostasis with ISRIB prevents pulmonary fibrosis

Aging is among the most important risk factors for the development of pulmonary fibrosis. We found that a small molecule that specifically inhibits translational inhibition induced by activation of the integrated stress response (ISRIB) attenuated the severity of pulmonary fibrosis in young and old mice. The more severe fibrosis in old compared to young mice was associated with increased recruitment of pathogenic monocyte-derived alveolar macrophages. Using genetic lineage tracing and transcriptomic profiling we found that ISRIB modulates stress response signaling in alveolar epithelial cells resulting in decreased apoptosis and decreased recruitment of pathogenic monocyte-derived alveolar macrophages. These data support multicellular model of fibrosis involving epithelial cells, pathogenic monocyte-derived alveolar macrophages and fibroblasts. Inhibition of the integrated stress response in the aging lung epithelium ameliorates pulmonary fibrosis by preventing the prolonged recruitment of monocyte-derived alveolar macrophages.

immunology↗

bioRxiv2019

The Aging Microenvironment Shapes Alveolar Macrophage Identity in Aging

A dysfunctional response to inhaled pathogens and toxins drives a substantial portion of the susceptibility to acute and chronic lung disease in the elderly. We used transcriptomic profiling combined with genetic lineage tracing, heterochronic adoptive transfer, parabiosis and treatment with metformin to show that the lung microenvironment defines the phenotype of long-lived alveolar macrophages during aging. While tissue-resident alveolar macrophages persist in the lung without input from monocytes over the lifespan, severe lung injury results in their replacement with monocyte-derived alveolar macrophages. These monocyte-derived alveolar macrophages are also shaped by the microenvironment both during aging and in response to a subsequent environmental challenge to become transcriptionally and functionally similar to tissue-resident alveolar macrophages. These findings show that changes in alveolar macrophage phenotypes during injury and aging are not cell autonomous but instead are shaped by changes in the aging lung microenvironment.

immunology↗

bioRxiv2019

Single-cell RNA-seq reveals spatially restricted multicellular fibrotic niches during lung fibrosis

Ontologically distinct populations of macrophages differentially contribute to organ fibrosis through unknown mechanisms. We applied lineage tracing, spatial methods and single-cell RNA-seq to a spatially-restricted model of asbestos-induced pulmonary fibrosis. We demonstrate that while tissue-resident interstitial macrophages, tissue-resident alveolar macrophages, and monocyte-derived alveolar macrophages are present in the fibrotic niche, only monocyte-derived alveolar macrophages are causally related to fibrosis. Monocyte-derived alveolar macrophages were specifically localized to fibrotic regions in the proximity of fibroblasts where they expressed molecules known to drive fibroblast proliferation, including PDGFA. Moreover, we identified autocrine M-CSF/M-CSFR signaling in monocyte-derived alveolar macrophages as a novel mechanism promoting their self-maintenance and persistence in the fibrotic niche. Pharmacological blockade of M-CSF signaling led to disappearance of the established population of monocyte-derived alveolar macrophages. Thus, our data indicate that monocyte-derived alveolar macrophages are specifically recruited to the fibrotic niche where they are maintained by autocrine signaling and drive fibrosis by stimulating fibroblast proliferation.

immunology↗

bioRxiv2018

Single-Cell Transcriptomic Analysis of Human Lung Reveals Complex Multicellular Changes During Pulmonary Fibrosis

Pulmonary fibrosis is a devastating disorder that results in the progressive replacement of normal lung tissue with fibrotic scar. Available therapies slow disease progression, but most patients go on to die or require lung transplantation. Single-cell RNA-seq is a powerful tool that can reveal cellular identity via analysis of the transcriptome, but its ability to provide biologically or clinically meaningful insights in a disease context is largely unexplored. Accordingly, we performed single-cell RNA-seq on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and one bronchoscopic cryobiospy sample. Integrated single-cell transcriptomic analysis of donors and patients with pulmonary fibrosis identified the emergence of distinct populations of epithelial cells and macrophages that were common to all patients with lung fibrosis. Analysis of transcripts in the Wnt pathway suggested that within the same cell type, Wnt secretion and response are restricted to distinct non-overlapping cells, which was confirmed using in situ RNA hybridization. Single-cell RNA-seq revealed heterogeneity within alveolar macrophages from individual patients, which was confirmed by immunohistochemistry. These results support the feasibility of discovery-based approaches applying next generation sequencing technologies to clinically obtained samples with a goal of developing personalized therapies.\n\nOne Sentence SummarySingle-cell RNA-seq applied to tissue from diseased and donor lungs and a living patient with pulmonary fibrosis identifies cell type-specific disease-associated molecular pathways.

systems biology↗