Publication Date:
2016-03-24
Description:
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 IRE1alpha. Once activated, IRE1alpha recruits TRAF2 to the ER membrane to initiate inflammatory responses via the NF-kappaB 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 IRE1alpha kinase inhibitor. The association of NOD1 and NOD2 with pro-inflammatory responses induced by the IRE1alpha/TRAF2 signalling pathway provides a novel link between innate immunity and ER-stress-induced inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869892/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869892/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Keestra-Gounder, A Marijke -- Byndloss, Mariana X -- Seyffert, Nubia -- Young, Briana M -- Chavez-Arroyo, Alfredo -- Tsai, April Y -- Cevallos, Stephanie A -- Winter, Maria G -- Pham, Oanh H -- Tiffany, Connor R -- de Jong, Maarten F -- Kerrinnes, Tobias -- Ravindran, Resmi -- Luciw, Paul A -- McSorley, Stephen J -- Baumler, Andreas J -- Tsolis, Renee M -- AI044170/AI/NIAID NIH HHS/ -- AI076246/AI/NIAID NIH HHS/ -- AI076278/AI/NIAID NIH HHS/ -- AI096528/AI/NIAID NIH HHS/ -- AI109799/AI/NIAID NIH HHS/ -- AI112258/AI/NIAID NIH HHS/ -- AI117303/AI/NIAID NIH HHS/ -- GM056765/GM/NIGMS NIH HHS/ -- R01 AI044170/AI/NIAID NIH HHS/ -- R01 AI076246/AI/NIAID NIH HHS/ -- R01 AI076278/AI/NIAID NIH HHS/ -- R01 AI096528/AI/NIAID NIH HHS/ -- R01 AI109799/AI/NIAID NIH HHS/ -- R21 AI112258/AI/NIAID NIH HHS/ -- R21 AI117303/AI/NIAID NIH HHS/ -- R25 GM056765/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Apr 21;532(7599):394-7. doi: 10.1038/nature17631. Epub 2016 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA. ; Center for Comparative Medicine, Schools of Medicine and Veterinary Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27007849" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Bacterial Outer Membrane Proteins/metabolism
;
Brucella abortus/immunology/pathogenicity
;
Cell Line
;
Dithiothreitol/pharmacology
;
Endoplasmic Reticulum/drug effects/pathology
;
*Endoplasmic Reticulum Stress/drug effects
;
Endoribonucleases/antagonists & inhibitors
;
Female
;
Humans
;
Immunity, Innate
;
Inflammation/chemically induced/*metabolism
;
Interleukin-6/biosynthesis
;
Male
;
Mice
;
Mice, Inbred C57BL
;
NF-kappa B/metabolism
;
Nod1 Signaling Adaptor Protein/immunology/*metabolism
;
Nod2 Signaling Adaptor Protein/immunology/*metabolism
;
Protein-Serine-Threonine Kinases/antagonists & inhibitors
;
Receptors, Pattern Recognition/metabolism
;
*Signal Transduction/drug effects
;
TNF Receptor-Associated Factor 2/metabolism
;
Taurochenodeoxycholic Acid/pharmacology
;
Thapsigargin/pharmacology
;
Unfolded Protein Response/drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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