Abstract
The NF-κB pathway has important roles in innate immune responses and its regulation is critical to maintain immune homeostasis. Here, we report a newly discovered feedback mechanism for the regulation of this pathway by TLR ligands in macrophages. Lipopolysaccharide (LPS) induced the expression of ICER via p38-mediated activation of CREB in macrophages. ICER, in turn, inhibited the transcriptional activity of NF-κB by direct interaction with the p65 subunit of NF-κB. Deficiency in ICER elevated binding of NF-κB to promoters of pro-inflammatory genes and their subsequent gene expression. Mice deficient in ICER were hypersensitive to LPS-induced endotoxic shock and showed propagated inflammation. Whereas ICER expression in ICER KO bone marrow transplanted mice rescued the ultra-inflammation phenotype, expression of a p65 binding-deficient ICER mutant failed to do so. Our results thus establish p38-CREB-ICER as key components of a negative feedback mechanism necessary to regulate TLR-driven inflammation.
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Acknowledgements
We thank Dr. Marc Montminy and Susan Hedrick (Salk Institute) for discussion and technical support. We thank Dr. Shogo Endo (Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology) for providing us with ICER KO mice. We thank Dr. Jerome V Karpiak (University of California San Diego School of Medicine, Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA) for English-language editing.
Author contributions
SL, JL, XQ, ZNZ, and BL designed and conducted the experiment and analyzed the data. BL wrote the manuscript. WL, CZ, and ZNZ designed the experiments and edited the manuscript. All authors read and approved the manuscript. BL is responsible for the integrity of the work as a whole.
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Lv, S., Li, J., Qiu, X. et al. A negative feedback loop of ICER and NF-κB regulates TLR signaling in innate immune responses. Cell Death Differ 24, 492–499 (2017). https://doi.org/10.1038/cdd.2016.148
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DOI: https://doi.org/10.1038/cdd.2016.148
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