Innate T-cell-derived IL-17A/F protects from bleomycin-induced acute lung injury but not bleomycin or adenoviral TGF-ß1-induced lung fibrosis in mice.

The pathobiology of IL-17 in lung fibrogenesis is controversial. Here we examined the role of IL-17A/F in bleomycin (BLM) and adenoviral TGF-ß1-induced lung fibrosis in mice. In both experimental models, WT and IL17af-/- mice showed increased collagen contents and remodeled lung architecture as assessed by histopathological examination, suggesting that IL-17A/F is dispensable for lung fibrogenesis. However, IL17af-/- mice responded to the BLM challenge with perturbed lung leukocyte subset recruitment. More specifically, bleomycin triggered angiocentric neutrophilic infiltrations of the lung accompanied by increased mortality of IL17af-/- but not WT mice. WT bone marrow transplantation failed to correct this phenotype in BLM-challenged IL17af-/- mice. Conversely, IL17a/f-/- bone marrow transplantation → WT did not perturb lung leukocytic responses upon BLM. At the same time, IL17af-/- mice treated with recombinant IL-17A/F showed an attenuated lung inflammatory response to BLM. Together, the data show that the degree of BLM-driven acute lung injury was critically dependent on the presence of IL-17A/F, while in both models, the fibrotic remodeling process was not.

B Cells Are Not Involved in the Regulation of Adenoviral TGF-ß1- or Bleomycin-Induced Lung Fibrosis in Mice.

Idiopathic pulmonary fibrosis (IPF) is an irreversible, age-related diffuse parenchymal lung disease of poorly defined etiology. Many patients with IPF demonstrate distinctive lymphocytic interstitial infiltrations within remodeled lung tissue with uncertain pathogenetic relevance. Histopathological examination of explant lung tissue of patients with IPF revealed accentuated lymphoplasmacellular accumulations in close vicinity to, or even infiltrating, remodeled lung tissue. Similarly, we found significant accumulations of B cells interfused with T cells within remodeled lung tissue in two murine models of adenoviral TGF-ß1 or bleomycin (BLM)-induced lung fibrosis. Such B cell accumulations coincided with significantly increased lung collagen deposition, lung histopathology, and worsened lung function in wild-type (WT) mice. Surprisingly, B cell-deficient µMT knockout mice exhibited similar lung tissue remodeling and worsened lung function upon either AdTGF-ß1 or BLM as for WT mice. Comparative transcriptomic profiling of sorted B cells collected from lungs of AdTGF-ß1- and BLM-exposed WT mice identified a large set of commonly regulated genes, but with significant enrichment observed for Gene Ontology terms apparently not related to lung fibrogenesis. Collectively, although we observed B cell accumulations in lungs of IPF patients as well as two experimental models of lung fibrosis, comparative profiling of characteristic features of lung fibrosis between WT and B cell-deficient mice did not support a major involvement of B cells in lung fibrogenesis in mice.