PDGFRα-positive fibroblasts display a proinflammatory phenotype in infection-driven exacerbation of experimental lung fibrosis

Idiopathic pulmonary fibrosis (IPF) is a severe diffuse parenchymal lung disease characterized by high mortality rates and poor prognosis. Patients with IPF can develop an acute worsening of the disease, named acute exacerbation (AE-IPF), which can be triggered by bacterial infections. Here we examined the proinflammatory contribution of PDGFRα-positive fibroblasts to S. pneumoniae (Spn) induced exacerbation of AdTGF-β1 induced lung fibrosis in mice. We found that numbers of PDGFRα- positive lung fibroblasts did not change substantially upon Spn driven worsening of established fibrosis. However, transcriptomic profiling along with single-cell RNA sequencing and proteomic profiling of flow-sorted fibroblasts showed a strong plasticity of fibroblast subsets developing a proinflammatory phenotype within 24 h after bacterial challenge. Remarkably, defined fibroblast subsets from AdTGF-β1+Spn treated mice exhibited strongly increased mRNA and protein levels of leukocyte-subset recruiting chemokines including CCL2, CXCL2, CXCL10, CXCL12 and CXCL13, but also other inflammation-related genes like Serum Amyloid A, Lipocalin 2, Haptoglobin, Tetherin, Mucin 16, Mesothelin, Osteopontin and Gremlin 1. At the same time, we found strongly increased TLR2 but not TLR4 mRNA levels in sorted fibroblasts of mice with Spn-driven fibrosis exacerbation. Collectively, the data suggest that in addition to their prominent role as ECM producing cells, subsets of fibroblasts appear to directly contribute to progression of lung fibrosis through the development of proinflammatory secretory phenotype.