TY - JOUR T1 - Integrated stress response restricts macrophage necroptosis JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202101260 VL - 5 IS - 1 SP - e202101260 AU - David E Place AU - Parimal Samir AU - RK Subbarao Malireddi AU - Thirumala-Devi Kanneganti Y1 - 2022/01/01 UR - https://www.life-science-alliance.org/content/5/1/e202101260.abstract N2 - The integrated stress response (ISR) regulates cellular homeostasis and cell survival following exposure to stressors. Cell death processes such as apoptosis and pyroptosis are known to be modulated by stress responses, but the role of the ISR in necroptosis is poorly understood. Necroptosis is an inflammatory, lytic form of cell death driven by the RIPK3-MLKL signaling axis. Here, we show that macrophages that have induced the ISR are protected from subsequent necroptosis. Consistent with a reduction in necroptosis, phosphorylation of RIPK1, RIPK3, and MLKL is reduced in macrophages pre-treated with ISR-inducing agents that are challenged with necroptosis-inducing triggers. The stress granule component DDX3X, which is involved in ISR-mediated regulation of pyroptosis, is not required for protecting ISR-treated cells from necroptosis. Disruption of stress granule assembly or knockdown of Perk restored necroptosis in pre-stressed cells. Together, these findings identify a critical role for the ISR in limiting necroptosis in macrophages. ER -