Aryl hydrocarbon receptor and hypoxia mediating inflammatory DCs in pulmonary fibrosis 3980

Abstract Description Idiopathic pulmonary fibrosis is a progressive, fibrotic disease with a prognosis of only 3-5 years of survival after diagnosis. The immune system and inflammation play a role in the development of fibrosis, but the sterile nature of IPF suggests dysregulated innate immunity. Our data demonstrate that type 1 dendritic cells (cDC1s) play an exacerbating role in our bleomycin-driven pulmonary fibrosis model. Complementary data shows that cDC1s express high levels of the transcription factor Aryl Hydrocarbon Receptor (AHR), which can act through both anti-inflammatory canonical pathways and pro-inflammatory noncanonical pathways. Our data suggest that during fibrogenesis, AHR is augmenting inflammation and contributing to worsening fibrosis, however the stimulus shunting AHR toward this non-canonical proinflammatory pathway is unclear. Canonical AHR activity and hypoxia-inducible pathways share a common mediator, suggesting a possible mechanism through which hypoxia and AHR may antagonize each other and influence inflammatory cDC1 functions. Using in vitro induced CD103+ DCs in a 1% O2 hypoxia chamber versus our standard normoxic incubator, we analyzed impact on DC signaling. Early studies suggest that hypoxia is decimating canonical AHR stimulation, however it is also eliminating inflammatory responses to TLR9 agonists. Thus, severe hypoxia does not appear to be recapitulating our in vivo findings. Studies to test other oxygen levels and other mechanisms are ongoing. Funding Sources This work has been supported by NIH T32GM007863-41 (HC), T32AI007413-28 (HC), R35HL144481-03 (BM), and by the Pulmoary Fibrosis Foundation Scholars Award (SG). Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)