The Antifibrotic Effects of α9 Integrin-targeted Therapy Through Inhibition of Fibrocyte and Fibroblast Activity

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Abstract [Background] Fibrocytes are mesenchymal progenitor cells that are derived from CD14-positive peripheral blood mononuclear cells. This cell population was reported to migrate into the injured lungs and contribute to fibrogenesis. However, any specific cell surface markers of these cells have not yet been identified. Recently, we reported that CD45+ CD11b+ CD11cintermediate Gr-1intermediate GFP+ cell population isolated from lung of collagen I(α)2-green fluorescent protein (Col-GFP) reporter mice administered bleomycin (BLM) contained highly purified pulmonary fibrocytes. In this study, we investigate functional molecules of this cell population, and the relationship between these molecules and the pathogenesis of lung fibrosis. [Methods] The high purity pulmonary fibrocyte cell population was clustered using single-cell RNA sequencing. Fibrocytes were isolated from mouse lung tissue. The effect of anti-α9 integrin antibodies on the migration of murine fibrocytes or fibroblasts was evaluated using a transwell assay. After murine fibrocytes or fibroblasts were stimulated with fibronectin containing EIIIA, which binds to α9 integrin, or anti-α9 integrin antibodies, the mRNA expression of profibrotic markers of fibrocytes were determined by quantitative PCR. [Results] Clustering of high purity pulmonary fibrocyte cell population using single-cell RNA-seq identified a collagen-expressing macrophage population that showed highly increased expression of α9 integrin. The stimulation with ligand of α9 integrin showed no effect on profibrotic mRNA expression in fibrocytes. However, Anti-α9 integrin antibody inhibited migration in not only murine fibrocytes but also murine fibroblasts. Furthermore, anti-α9 integrin antibody decreased Acta2 expression in fibroblasts, but not in fibrocytes. [Conclusion] These results suggest that α9 integrin signaling is involved in the functions of fibrocytes and fibroblasts. Anti-α9 integrin antibody may be a novel candidate for the treatment of pulmonary fibrosis.

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