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Limiting inflammation—the negative regulation of NF-κB and the NLRP3 inflammasome

Abstract

A properly mounted immune response is indispensable for recognizing and eliminating danger arising from foreign invaders and tissue trauma. However, the 'inflammatory fire' kindled by the host response must be tightly controlled to prevent it from spreading and causing irreparable damage. Accordingly, acute inflammation is self-limiting and is normally attenuated after elimination of noxious stimuli, restoration of homeostasis and initiation of tissue repair. However, unresolved inflammation may lead to the development of chronic autoimmune and degenerative diseases and cancer. Here, we discuss the key molecular mechanisms that contribute to the self-limiting nature of inflammatory signaling, with emphasis on the negative regulation of the NF-κB pathway and the NLRP3 inflammasome. Understanding these negative regulatory mechanisms should facilitate the development of much-needed therapeutic strategies for treatment of inflammatory and autoimmune pathologies.

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Figure 1: Mechanisms involved in the negative feedback regulation of proinflammatory NF-κB signaling.
Figure 2: Regulation of TNFR1-induced NF-κB signaling by ubiquitination and phosphorylation.
Figure 3: The NLRP3 inflammasome and its regulation.

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Acknowledgements

Work in the laboratory of R.B. is supported by grants from the VIB, the Fund for Scientific Research Flanders (FWO), the Foundation Against Cancer and Ghent University (Concerted Research Actions, GOA). I.S.A. is supported by an FWO postdoctoral fellowship and an FWO research grant. Z.Z. was supported by a Cancer Research Irvington Postdoctoral Fellowship, a Prevent Cancer Foundation Board of Directors Award and an American Association for the Study of Liver Diseases (AASLD) Pinnacle Research Award. Research was supported by grants from the NIH (AI043477 and CA163798) to M.K., the Leukemia and Lymphoma Society SCOR (20132569) to M.K. and the Alliance for Lupus Research (257214) to M.K., who is supported as an American Cancer Research Professor and as the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.

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Correspondence to Rudi Beyaert.

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Afonina, I., Zhong, Z., Karin, M. et al. Limiting inflammation—the negative regulation of NF-κB and the NLRP3 inflammasome. Nat Immunol 18, 861–869 (2017). https://doi.org/10.1038/ni.3772

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