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Regulation of tissue homeostasis by NF-κB signalling: implications for inflammatory diseases

Nature Reviews Immunology volume 9, pages 778–788 (2009)Cite this article

Key Points

  • The nuclear factor-κB (NF-κB) signalling pathway regulates immune and inflammatory responses and has been implicated in the pathogenesis of several inflammatory diseases and cancer. NF-κB promotes inflammation and immunity against pathogens by regulating the expression of pro-inflammatory molecules, including cytokines, chemokines, adhesion molecules and proteins with antimicrobial activity. At the same time, NF-κB protects cells from death by inducing the expression of anti-apoptotic and antioxidant proteins.

  • NF-κB inhibition is thought to be anti-inflammatory; however, recent experiments in mouse models have shown that NF-κB inhibition in epithelial cells can result in the spontaneous development of chronic inflammatory conditions. These results indicated that NF-κB acts in non-immune cells to control the maintenance of tissue immune homeostasis.

  • Mice with epidermal keratinocyte-specific inhibition of NF-κB signalling — achieved by ablation of inhibitor of NF-κB (IκB) kinase-β (IKKβ), NEMO (NF-κB essential modulator) or TAK1 (transforming growth factor-β-activated kinase 1) or by transgenic expression of a degradation-resistant form of IκBα — develop severe inflammatory hyperplastic skin lesions that depend on tumour necrosis factor (TNF) signalling.

  • Complete inhibition of canonical NF-κB signalling in intestinal epithelial cells (IECs) by ablation of NEMO or both IKKα and IKKβ resulted in the development of severe chronic colon inflammation in mice. MYD88-dependent signals were required for the development of colitis, which indicates that bacterial recognition by Toll-like receptors (TLRs) could provide the pathogenic signals. Blockade of TNF receptor signalling also inhibits colon inflammation in these mice, which supports a crucial role for TNF in colitis pathogenesis.

  • Mice with liver parenchymal cell (LPC)-specific ablation of NEMO develop spontaneous steatohepatitis and hepatocellular carcinoma. Disease pathogenesis in this model requires FADD (FAS-associated via death domain)-dependent signals and is blocked by feeding of antioxidant compounds, which indicates that death receptor signalling and oxidative stress contribute to disease pathogenesis.

  • The outcome of NF-κB inhibition depends on the level of inhibition achieved. Complete blockade of canonical NF-κB signalling is only achieved by ablation of NEMO or of both IKKα and IKKβ, which have some degree of functional redundancy.

  • NF-κB inhibition in cells that are exposed to environmental insults resulted in spontaneous inflammation, whereas NF-κB inhibition in cells that are not normally exposed to environmental challenges did not cause pathology. These findings indicate that NF-κB signalling might have a special function in epithelia that are constantly exposed to environmental challenges, which is essential for the maintenance of physiological immune homeostasis.

Abstract

The nuclear factor-κB (NF-κB) signalling pathway regulates immune responses and is implicated in the pathogenesis of many inflammatory diseases. Given the well established pro-inflammatory functions of NF-κB, inhibition of this pathway would be expected to have anti-inflammatory effects. However, recent studies in mouse models have led to surprising and provocative results, as NF-κB inhibition in epithelial cells resulted in the spontaneous development of severe chronic inflammatory conditions. These findings indicate that NF-κB signalling acts in non-immune cells to control the maintenance of tissue immune homeostasis. This Review discusses the mechanisms by which NF-κB activity in non-immune cells regulates tissue immune homeostasis and prevents the pathogenesis of inflammatory diseases.

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Figure 1: Schematic depiction of the canonical NF-κB signalling pathway.
Figure 2: NF-κB inhibition in epidermal keratinocytes disturbs skin immune homeostasis.
Figure 3: NF-κB inhibition in intestinal epithelial cells disturbs intestinal immune homeostasis and causes chronic colitis.
Figure 4: NF-κB inhibition in liver parenchymal cells causes hepatitis and hepatocellular carcinoma.
Figure 5: Balanced NF-κB signalling is essential for the maintenance of immune homeostasis.

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Acknowledgements

I am indebted to all the present and past members of my laboratory for making this work possible. Work in my laboratory is supported by funding from the University of Cologne (Germany), the Human Frontier Science Program, the Deutsche Forschungsgemeinschaft and the European Union.

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  1. Institute of Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Strasse 47, Cologne, 50674, Germany

    Manolis Pasparakis

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Pasparakis, M. Regulation of tissue homeostasis by NF-κB signalling: implications for inflammatory diseases. Nat Rev Immunol 9, 778–788 (2009). https://doi.org/10.1038/nri2655

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