Immunology Making a Bid for Inflammation

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

The innate immune response depends on the recognition of pathogen-associated patterns by host factors such as Toll-like receptors and nucleotide-binding and oligomerization domain (NOD) proteins, which trigger inflammation. NOD1 and NOD2 recognize peptidoglycans from bacteria and induce antimicrobial and inflammatory responses in the intestine. Dysregulation of NOD signaling results in inflammatory bowel disease. Yeretssian et al. performed a small interfering RNA (siRNA) screen and network analysis so as to identify proteins that regulated the NOD1 pathway in HT29 cells, a human intestinal epithelial cell line. They identified BID, a BH3-only Bcl2 family member, which promotes apoptosis, as a positive regulator of NOD1 signaling. BID was required for the production of interleukin-8 (IL-8) by HT29 cells in response to the NOD1 agonist Tri-DAP. Deletion of Bid in mouse macrophages prevented the activation of extracellular signal–regulated kinase (ERK) and nuclear factor B (NF-B) and the production of proinflammatory cytokines by NOD1- and NOD2-specific agonists. These responses were restored by providing Bid^–/– cells with exogenous full-length BID or a BID mutant that was unable to promote apoptosis. Coimmunoprecipitation experiments showed that BID physically interacted with NOD1 and NOD2, as well as with the inhibitor of NF-B (IB) kinase (IKK) complex. NOD agonists protected wild-type, but not Bid^–/–, mice from experimentally induced colitis, and Bid^–/– mice exhibited a muted inflammatory response as compared with that of wild-type mice. Together, these data suggest that BID mediates the effects of NOD signaling independently of its role in apoptosis, providing a potential therapeutic target in inflammatory bowel disease.

G. Yeretssian, R. G. Correa, K. Doiron, P. Fitzgerald, C. P. Dillon, D. R. Green, J. C. Reed, M. Saleh, Non-apoptotic role of BID in inflammation and innate immunity. Nature 474, 96–99 (2011). [PubMed]