Phenotypic Analysis of Fibrogenic Monocyte/Macrophage Subsets in Acute Inflammatory Exacerbations of Lung Disease Driven by Mutant Surfactant Protein-C Expression
Journal of Immunology(2023)
Abstract
Abstract Acute inflammatory exacerbations (AIE) represent precipitous deteriorations of a number of chronic lung conditions, including pulmonary fibrosis (PF), COPD, and asthma. AIEs are marked by diffuse and persistent polycellular alveolitis that profoundly accelerate lung function decline and mortality. Excess monocyte mobilization during AIE, and their persistence in the lung are linked to poor disease outcome. Guided by clinical evidence, we have developed an inducible model of pulmonary fibrosis leveraging the PF-linked missense isoleucine to threonine mutation at position 73 [I73T] in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene [SFTPC]. We have previously shown that ablation of CCR2+ monocytes was protective with respect to lung histopathology, mouse survival, and overall inflammation following SP-C mutant induction. Here we identify and phenotypically characterize resident and recruited monocytes/macrophages populations intervening during the initiation and progression of AIE-PF. Single cell sequencing shows pro-inflammatory and pro-fibrotic signatures originating from immature recruited clusters (itgax-itgam+ ccr2+ cx3cr1+)as well as activated macrophages (cd68+ itgax+ itgam+ arg1+)14 d after SP-C I73Tinduction. Using CellChat Explorer database, these cells were predicted to coordinate intense tgfb1, fn1/fibronectinand spp1/osteopontinsignaling. Together, these results provide a clear picture of the fibrogenic role of specific activated monocyte/macrophage subsets responding to alveolar epithelial stress. NIEHS R01ES032553 (AV); ALSAM Foundation for Research Initiatives Grant (AV)
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Key words
fibrogenic monocyte/macrophage,monocyte/macrophage subsets,lung disease,acute inflammatory exacerbations
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