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.
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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 Articles. 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.