ATF4 orchestrates IL-1α-induced senescence in adult neural stem cells

Abstract

Adult neural stem cells (NSC) are a potential source for the regeneration of damaged tissue during neuropathological conditions, but much remains unexplored. In an attempt to study the influence of neuroinflammation on NSCs, we generated a transgenic reporter rat strain that expresses the Discosoma sp. red (DsRed) fluorophore in NSCs and subjected it to traumatic brain injury (TBI). Transcriptomic analysis of NSCs isolated from TBI revealed an enrichment of stress response genes that pertained to endoplasmic reticulum (ER) stress and integrated stress response (ISR). Downstream analysis on NSC cultures pinpointed IL-1 as a trigger of ISR in these cells. At concentration levels similar to the ones measured post-TBI in rats, IL-1 induced the translation of activating transcription factor 4 (ATF4), an ISR master regulator. Further, ATF4 was necessary for the IL-1 -dependent induction of a senescent profile in NSCs, which included a metabolic shift towards glycolysis, induction of senescence-associated secretory phenotype, SASP, and cell cycle arrest. In summary, the ISR/ATF4 pathway seems to play a major role in NSC function during neuroinflammation and provides a therapeutic tool for protecting the NSC pool during these conditions.