The integrated stress response, a novel mediator of pro-inflammatory microglia

Abstract Microglia undergo a dynamic pro-inflammatory phenotypic shift in response to acute injury and disease. However, inappropriate microglia reactivity impairs homeostatic resolution and exacerbates neurodegeneration. The integrated stress response (ISR) is a putative signalling pathway that mediates both intrinsic and extracellular stress. Thus, the ISR is an attractive target for investigation as a novel modulator of microglia reactivity. In the present study, ISR activation is stimulated through toxin-mediated perturbations to proteostasis, validating the efficacy of pharmacological ISR inhibition in primary microglia in vitro. This study demonstrates that ISR-dependent, non-canonical priming and inflammasome activation are sufficient to induce the release of pro-inflammatory cytokines and paracrine stimulation of naïve microglia. Furthermore, ISR inhibition rescues survival, homeostatic morphology, and upregulation of phagocytic activity. These results suggest that the ISR is a novel effector of microglial activation. Therapeutic ISR manipulation may be a tangible target for mediating microglia behaviour, restoring brain homeostasis, and mitigating the deleterious effects of sustained neuroinflammation.