NOD1 and NOD2 signalling links ER stress with inflammation

A. Marijke Keestra-Gounder, Mariana X. Byndloss, Núbia Seyffert, Briana M. Young, Alfredo Chávez-Arroyo, April Y. Tsai, Stephanie A. Cevallos, Maria G. Winter, Oanh H. Pham, Connor R. Tiffany, Maarten F. De Jong, Tobias Kerrinnes, Resmi Ravindran, Paul A Luciw, Stephen J Mcsorley, Andreas J Baumler, Renee M Tsolis

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167 Scopus citations

Abstract

Endoplasmic reticulum (ER) stress is a major contributor to inflammatory diseases, such as Crohn disease and type 2 diabetes. ER stress induces the unfolded protein response, which involves activation of three transmembrane receptors, ATF6, PERK and IRE1α. Once activated, IRE1α recruits TRAF2 to the ER membrane to initiate inflammatory responses via the NF-IκB pathway. Inflammation is commonly triggered when pattern recognition receptors (PRRs), such as Toll-like receptors or nucleotide-binding oligomerization domain (NOD)-like receptors, detect tissue damage or microbial infection. However, it is not clear which PRRs have a major role in inducing inflammation during ER stress. Here we show that NOD1 and NOD2, two members of the NOD-like receptor family of PRRs, are important mediators of ER-stress-induced inflammation in mouse and human cells. The ER stress inducers thapsigargin and dithiothreitol trigger production of the pro-inflammatory cytokine IL-6 in a NOD1/2-dependent fashion. Inflammation and IL-6 production triggered by infection with Brucella abortus, which induces ER stress by injecting the type IV secretion system effector protein VceC into host cells, is TRAF2, NOD1/2 and RIP2-dependent and can be reduced by treatment with the ER stress inhibitor tauroursodeoxycholate or an IRE1α kinase inhibitor. The association of NOD1 and NOD2 with pro-inflammatory responses induced by the IRE1α/TRAF2 signalling pathway provides a novel link between innate immunity and ER-stress-induced inflammation.

Original languageEnglish (US)
Pages (from-to)394-397
Number of pages4
JournalNature
Volume532
Issue number7599
DOIs
StatePublished - Apr 21 2016

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ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Keestra-Gounder, A. M., Byndloss, M. X., Seyffert, N., Young, B. M., Chávez-Arroyo, A., Tsai, A. Y., Cevallos, S. A., Winter, M. G., Pham, O. H., Tiffany, C. R., De Jong, M. F., Kerrinnes, T., Ravindran, R., Luciw, P. A., Mcsorley, S. J., Baumler, A. J., & Tsolis, R. M. (2016). NOD1 and NOD2 signalling links ER stress with inflammation. Nature, 532(7599), 394-397. https://doi.org/10.1038/nature17631