| First Author | Sarhan J | Year | 2019 |
| Journal | Cell Death Differ | Volume | 26 |
| Issue | 2 | Pages | 332-347 |
| PubMed ID | 29786074 | Mgi Jnum | J:275025 |
| Mgi Id | MGI:6305773 | Doi | 10.1038/s41418-018-0122-7 |
| Citation | Sarhan J, et al. (2019) Constitutive interferon signaling maintains critical threshold of MLKL expression to license necroptosis. Cell Death Differ 26(2):332-347 |
| abstractText | 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. |
