NOD1/NOD2 signaling links ER stress with inflammation

Endoplasmic reticulum (ER) stress is a major contributor to inflammatory diseases, such as Crohn's disease and type 2 diabetes(1,2). ER stress induces the unfolded protein response (UPR), which involves activation of three transmembrane receptors, ATF6 (activating transcription factor 6), PERK (protein kinase RNA-like endoplasmic reticulum kinase) and IRE1 alpha (inositol-requiring enzyme 1 alpha)(3) (Extended Data figure 1 alpha). Once activated, IRE1a recruits TRAF2 (TNF receptor-associated factor 2) to the ER membrane to initiate inflammatory responses via the nuclear factor kappa B (NF-kappa B) pathway(4). Inflammation is commonly triggered when pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) or nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), detect tissue damage or microbial infection. However, it is not clear which PRRs play a major role in inducing inflammation during ER stress. Here we show that NOD1 and NOD2, two members of the NLR family of PRRs, are important mediators of ER stress-induced inflammation. The ER stress inducers thapsigargin and dithiothreitol (DTT) triggered production of the pro-inflammatory cytokine interleukin (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 (T4SS) effector protein VceC into host cells(5), was TRAF2, NOD1/2 and RIP2-dependent and could be blunted by treatment with the ER-stress inhibitor tauroursodeoxycholate (TUDCA) or an IRE1 alpha kinase inhibitor. The association of NOD1 and NOD2 with pro-inflammatory responses induced by the IRE1 alpha/TRAF2 signaling pathway provides a novel link between innate immunity and ER stress-induced inflammation.