Publication Date:
2011-05-10
Description:
Innate immunity is a fundamental defence response that depends on evolutionarily conserved pattern recognition receptors for sensing infections or danger signals. Nucleotide-binding and oligomerization domain (NOD) proteins are cytosolic pattern-recognition receptors of paramount importance in the intestine, and their dysregulation is associated with inflammatory bowel disease. They sense peptidoglycans from commensal microorganisms and pathogens and coordinate signalling events that culminate in the induction of inflammation and anti-microbial responses. However, the signalling mechanisms involved in this process are not fully understood. Here, using genome-wide RNA interference, we identify candidate genes that modulate the NOD1 inflammatory response in intestinal epithelial cells. Our results reveal a significant crosstalk between innate immunity and apoptosis and identify BID, a BCL2 family protein, as a critical component of the inflammatory response. Colonocytes depleted of BID or macrophages from Bid(-/-) mice are markedly defective in cytokine production in response to NOD activation. Furthermore, Bid(-/-) mice are unresponsive to local or systemic exposure to NOD agonists or their protective effect in experimental colitis. Mechanistically, BID interacts with NOD1, NOD2 and the IkappaB kinase (IKK) complex, impacting NF-kappaB and extracellular signal-regulated kinase (ERK) signalling. Our results define a novel role of BID in inflammation and immunity independent of its apoptotic function, furthering the mounting evidence of evolutionary conservation between the mechanisms of apoptosis and immunity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yeretssian, Garabet -- Correa, Ricardo G -- Doiron, Karine -- Fitzgerald, Patrick -- Dillon, Christopher P -- Green, Douglas R -- Reed, John C -- Saleh, Maya -- MOP 82801/Canadian Institutes of Health Research/Canada -- England -- Nature. 2011 Jun 2;474(7349):96-9. doi: 10.1038/nature09982. Epub 2011 May 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21552281" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Apoptosis/immunology
;
BH3 Interacting Domain Death Agonist Protein/genetics/*immunology
;
Colitis/genetics/immunology
;
Epithelial Cells/*immunology
;
HEK293 Cells
;
HT29 Cells
;
Humans
;
I-kappa B Kinase/immunology
;
Immunity, Innate/*genetics
;
Inflammation/*genetics
;
Intestinal Mucosa/*immunology
;
Mice
;
Mice, Inbred C57BL
;
Nod1 Signaling Adaptor Protein/immunology
;
Nod2 Signaling Adaptor Protein/immunology
;
RNA Interference
;
Signal Transduction/genetics/immunology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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