Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients die from the disease within 2–5 years. The molecular pathogenesis underlying the immunologic changes that occur in IPF is poorly understood. We characterize noncanonical aryl-hydrocarbon receptor (ncAHR) signaling in DCs as playing a role in the production of IL-6 and increased IL-17+ cells, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2, which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing mice harboring a floxed AHR exon 2 deletion (AHRΔex2) with mice harboring a CD11c-Cre. Bleomycin (blm) was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex vivo with relevant TLR agonists and AHR-modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis; however, AHRΔex2 mice treated with blm developed more fibrosis, and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2, and fibrotic fibroblasts activated IL-6 production in CD103+ DCs. Study of human samples corroborated the relevance of these findings in patients with IPF. We also show, for the first time to our knowledge, that AHR exon 2 floxed mice retain the capacity for ncAHR signaling.
Authors
Hannah Carter, Rita Medina Costa, Taylor S. Adams, Talon M. Gilchrist, Claire E. Emch, Monica Bame, Justin M. Oldham, Steven K. Huang, Angela L. Linderholm, Imre Noth, Naftali Kaminski, Bethany B. Moore, Stephen J. Gurczynski
Figure 4
Loss of canonical AHR signaling in CD103+ DCs exacerbates fibrosis via a ncAHR-dependent mechanism.
