1. Academic Validation
  2. Integrated stress response restricts macrophage necroptosis

Integrated stress response restricts macrophage necroptosis

  • Life Sci Alliance. 2021 Nov 11;5(1):e202101260. doi: 10.26508/lsa.202101260.
David E Place 1 Parimal Samir 1 Rk Subbarao Malireddi 1 Thirumala-Devi Kanneganti 2
Affiliations

Affiliations

  • 1 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 2 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA [email protected].
Abstract

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.

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