Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice

Ning Li, Xuefeng Wu, Ryan G. Holzer, Jun Hee Lee, Jelena Todoric, Eek Joong Park, Hisanobu Ogata, Anna S. Gukovskaya, Ilya Gukovsky, Donald P. Pizzo, Scott VandenBerg, David Tarin, Çiǧdem Atay, Melek C. Arkan, Thomas J. Deerinck, Jorge Moscat, Maria Diaz-Meco, David Dawson, Mert Erkan, Jörg KleeffMichael Karin

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Abstract

Chronic pancreatitis is an inflammatory disease that causes progressive destruction of pancreatic acinar cells and, ultimately, loss of pancreatic function. We investigated the role of IKB kinase α (IKKα) in pancreatic homeostasis. Pancreas-specific ablation of IKKa (Ikkα Δpan) caused spontaneous and progressive acinar cell vacuolization and death, interstitial fibrosis, inflammation, and circulatory release of pancreatic enzymes, clinical signs resembling those of human chronic pancreatitis. Loss of pancreatic IKKα causes defective autophagic protein degradation, leading to accumulation of p62-mediated protein aggregates and enhanced oxidative and ER stress in acinar cells, but none of these effects is related to NF-κB. Pancreas-specific p62 ablation prevented ER and oxidative stresses and attenuated pancreatitis in Ikkα Δpan mice, suggesting that cellular stress induced by p62 aggregates promotes development of pancreatitis. Importantly, downregulation of IKKα and accumulation of p62 aggregates were also observed in chronic human pancreatitis. Our studies demonstrate that IKKα, which may control autophagic protein degradation through its interaction with ATG16L2, plays a critical role in maintaining pancreatic acinar cell homeostasis, whose dysregulation promotes pancreatitis through p62 aggregate accumulation.

Original languageEnglish
Pages (from-to)2231-2243
Number of pages13
JournalJournal of Clinical Investigation
Volume123
Issue number5
DOIs
Publication statusPublished - May 1 2013

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Li, N., Wu, X., Holzer, R. G., Lee, J. H., Todoric, J., Park, E. J., Ogata, H., Gukovskaya, A. S., Gukovsky, I., Pizzo, D. P., VandenBerg, S., Tarin, D., Atay, Ç., Arkan, M. C., Deerinck, T. J., Moscat, J., Diaz-Meco, M., Dawson, D., Erkan, M., ... Karin, M. (2013). Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice. Journal of Clinical Investigation, 123(5), 2231-2243. https://doi.org/10.1172/JCI64498