Program in Innate Immunity; Department of Medicine, Division of Infectious Diseases and Immunology
Cell Biology | Cellular and Molecular Physiology | Hemic and Immune Systems | Immunity | Immunopathology
Interferons (IFNs) are critical determinants in immune-competence and autoimmunity, and are endogenously regulated by a low-level constitutive feedback loop. However, little is known about the functions and origins of constitutive IFN. Recently, lipopolysaccharide (LPS)-induced IFN was implicated as a driver of necroptosis, a necrotic form of cell death downstream of receptor-interacting protein (RIP) kinase activation and executed by mixed lineage kinase like-domain (MLKL) protein. We found that the pre-established IFN status of the cell, instead of LPS-induced IFN, is critical for the early initiation of necroptosis in macrophages. This pre-established IFN signature stems from cytosolic DNA sensing via cGAS/STING, and maintains the expression of MLKL and one or more unknown effectors above a critical threshold to allow for MLKL oligomerization and cell death. Finally, we found that elevated IFN-signaling in systemic lupus erythematosus (SLE) augments necroptosis, providing a link between pathological IFN and tissue damage during autoimmunity.
Rights and Permissions
Copyright © ADMC Associazione Differenziamento e Morte Cellulare 2018. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
Cell Death Differ. 2019 Jan;26(2):332-347. doi: 10.1038/s41418-018-0122-7. Epub 2018 May 21. Link to article on publisher's site
Cell death and differentiation
Sarhan J, Liu BC, Muendlein HI, Weindel CG, Smirnova I, Tang AY, Ilyukha V, Sorokin M, Buzdin A, Fitzgerald KA, Poltorak A. (2019). Constitutive interferon signaling maintains critical threshold of MLKL expression to license necroptosis. Open Access Publications by UMass Chan Authors. https://doi.org/10.1038/s41418-018-0122-7. Retrieved from https://escholarship.umassmed.edu/oapubs/3745
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.