Macrophage-derived lipid mediators play pivotal autocrine/paracrine roles in resolution and repair. In the alveolar niche, ?regenerative fibroblasts? produce vital growth factors (FGF7/10) for alveolar stem cells to regenerate damaged epithelia, however the signals controlling fibroblast phenotype are yet to be defined.
Aim: To investigate the role of macrophage-derived PGE2, specialized pro-resolving mediators (SPMs) and growth factors in controlling interstitial fibroblast phenotype during regeneration of alveolar injury.
IPF myofibroblasts were treated with PGE2 and studied by RNAseq. IPF BAL macrophages were treated with PGE2 and analysed in a fibrosis and resolution-focused QuantiGene assay. Further, to investigate the regenerative potential of lipid mediators in the macrophage-fibroblast-epithelial cell axis, we are developing 3D co-culture systems integrating macrophage signals, fibroblasts and lung progenitors.
Results: PGE2 reverted myofibroblast phenotype, re-activated expression of FGF7/10, and upregulated markers of lipofibroblasts and matrix fibroblasts (TCF21 and COL14A1), while reducing myofibroblast genes (ACTA2, COL1A1 and SERPINE1) and genes involved in the Serine - Glycine synthesis pathway (PHGDH, PSAT1, PSPH and SHMT2). Similarly, PGE2 inhibited pro-fibrotic signals such as SERPINE1 and CCL24 from IPF BAL macrophages and enhanced expression of THBS1, AREG and VEGFA known to increase efferocytotic capacity, drive fibroblasts FGF7/10 and to support vascular regeneration, respectively.
Our data support a model where macrophage signals controlling fibroblast phenotype have the potential to restrict fibrosis in IPF and activate regeneration of the alveolar niche.