Bcl10 synergistically links CEACAM3 and TLR‐dependent inflammatory signalling |
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| Authors: | Helen Sarantis Tak W Mak Michael Glogauer Scott D Gray‐Owen |
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| Affiliation: | 1. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada;2. The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada;3. Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada |
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| Abstract: | The neutrophil‐specific innate immune receptor CEACAM3 functions as a decoy to capture Gram‐negative pathogens, such as Neisseria gonorrhoeae, that exploit CEACAM family members to adhere to the epithelium. Bacterial binding to CEACAM3 results in their efficient engulfment and triggers activation of an nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB)‐dependent inflammatory response by human neutrophils. Herein, we report that CEACAM3 cross‐linking is not sufficient for induction of cytokine production and show that the inflammatory response induced by Neisseria gonorrhoeae infection is elicited by an integration of signals from CEACAM3 and toll‐like receptors. Using neutrophils from a human CEACAM‐expressing mouse line (CEABAC), we use a genetic approach to reveal a molecular bifurcation of the CEACAM3‐mediated antimicrobial and inflammatory responses. Ex vivo experiments with CEABAC‐Rac2?/?, CEABAC‐Bcl10?/?, and CEABAC‐Malt1?/? neutrophils indicate that these effectors are not necessary for gonococcal engulfment, yet all 3 effectors contribute to CEACAM3‐mediated cytokine production. Interestingly, although Bcl10 and Malt1 are often inextricably linked, Bcl10 enabled synergy between toll‐like receptor 4 and CEACAM3, whereas Malt1 did not. Together, these findings reveal an integration of the specific innate immune receptor CEACAM3 into the network of more conventional pattern recognition receptors, providing a mechanism by which the innate immune system can unleash its response to a relentless pathogen. |
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| Keywords: | Bcl10 CEACAM3 Malt1 Neisseria gonorrhoeae neutrophil TLR4 |
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