Role of CCR2+ Myeloid Cells in Inflammatory Responses Driven by Mutation in Surfactant Protein-C Expression

ABSTRACT: Acute inflammatory exacerbations (AIE) represent precipitous deteriorations of a number of chronic lung conditions, including pulmonary fibrosis (PF), chronic obstructive pulmonary disease and asthma. AIEs are marked by diffuse and persistent polycellular alveolitis that profoundly accelerate lung function decline and mortality. In particular, excess monocyte mobilization during AIE and their persistence in the lung have been suggested to be linked to poor disease outcome. We have developed a mutant model of pulmonary fibrosis leveraging the PF-linked missense isoleucine to threonine substitution at position 73 [I73T] in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene [SFTPC]. With this toolbox at hand, the present work investigates the dynamics of resident alveolar macrophages and peripheral monocytes during the initiation and progression of AIE-PF. FACS analysis of SigF+CD11b- alveolar macrophages and Ly6Chi monocytes isolated 3 d and 14 d after SP-CI73T injury and performed RNA sequencing. Pathway and gene expression analysis revelaed dynamic transcriptional changes associated with “Innate Immunity’ and ‘Extracellular Matrix Organization’ signaling. Supported by previous pharmacological evidence, genetic ablation of CCR2+ monocytes (SP-CI73TCCR2KO) resulted in improved lung histology, mouse survival, and reduced inflammation compared to SP-CI73TCCR2WT cohorts. Immunohistochemical and in situ hybridization analysis revealed comparable levels of tgfb1 mRNA expression localized primarily parenchymal cells found nearby foci of injury. Our results also confirmed reduced inflammatory activation (iNOS, Arg1) in SP-CI73TCCR2KO lungs as well as partial colocalization of tgfb1 mRNA expression in Arg1+ cells. These results provide a detailed picture on the role of resident macrophages and recruited monocytes in the context of AIE-PF driven by alveolar epithelial dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE166300 | GEO | 2021/02/07

REPOSITORIES: GEO