The Integrated stress response, a novel mediator of pro-inflammatory microglia phenotypes
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 mediating 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 via toxin-mediated perturbations to proteostasis and validate 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 pro-inflammatory cytokines release and paracrine stimulation of naïve microglia—further, ISR inhibition rescues survival, homeostatic morphology, and upregulation in phagocytic activity. These results implicate the ISR as a novel affecter 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.