A transcriptional atlas of gut-innervating neurons reveals activation of interferon signaling and ferroptosis during intestinal inflammation
Patrycja M. Forster, Manuel O. Jakob, Dilmurat Yusuf, Marvin Bubeck, Heidi Limberger, Yanjiang Luo, Paula Thieme, Alexandra Polici, Nele Sterczyk, Sotiria Boulekou, Laura P. Bartel, Catalina Cosovanu, Mario Witkowski, Miguel González-Acera, Anja A. Kühl, Carl Weidinger, Imke Atreya, Raja Atreya, Petra Bacher, Christoph Becker, Christian Bojarski, Nathalie Britzen-Laurent, Caroline Bosch-Voskens, Hyun-Dong Chang, Andreas Diefenbach, Claudia Günther, Ahmed N. Hegazy, Kai Hildner, Christoph S.N. Klose, Kristina Koop, Susanne Krug, Anja A. Kühl, Moritz Leppkes, Rocío López-Posadas, Leif S.-H. Ludwig, Clemens Neufert, Markus Neurath, Jay V. Patankar, Magdalena Prüß, Andreas Radbruch, Chiara Romagnani, Francesca Ronchi, Ashley Sanders, Alexander Scheffold, Jörg-Dieter Schulzke, Michael Schumann, Sebastian Schürmann, Britta Siegmund, Michael Stürzl, Zlatko Trajanoski, Antigoni Triantafyllopoulou, Maximilian Waldner, Carl Weidinger, Stefan Wirtz, Sebastian Zundler, Rolf Backofen, Ahmed N. Hegazy, Jay V. Patankar, Christoph S.N. Klose
Abstract
Enteric infections often cause long-term sequelae, including persistent gastrointestinal symptoms, such as pain, discomfort, or irritable bowel syndrome. The plethora of sensory symptoms indicates that gut-innervating neurons might be directly affected by inflammation. However, sequencing studies of neurons in the gastrointestinal tract are hampered by difficulties in purifying neurons, especially during inflammation. Activating a nuclear GFP tag selectively in neurons enabled sort purification of intrinsic and extrinsic neurons of the gastrointestinal tract in models of intestinal inflammation. Using bulk and single-nucleus RNA sequencing, we mapped the whole transcriptomic landscape and identified a conserved neuronal response to inflammation, which included the interferon signaling and ferroptosis pathway. Deletion of the interferon receptor 1 in neurons regulated ferroptosis, neuronal loss, and consequently gut-transit time. Collectively, this study offers a resource documenting neuronal adaptation to inflammatory conditions and exposes the interferon and ferroptosis pathways as signaling cascades activated in neurons during inflammation.