Restraint of inflammasome-driven cytokine responses through the mRNA stability protein TTP

Stimulation of the NLRP3 inflammasome causes a massive disruption of cellular homeostasis, with Golgi disruption, mitochondrial dysfunction, and changes in intracellular ion concentration all occurring rapidly upon stimulation. Given this, it would seem near certain that these changes might also globally affect cellular signaling pathways, yet few, if any, studies have explored this possibility. Here, we combine genomics and phosphoproteomics to identify a major disruption in the ERK1/2 MAP kinase signaling cascade upon inflammasome stimulation. This loss of ERK1/2 activity results in rapid inactivation of the mRNA decay-promoting protein tristetraprolin (TTP), with loss of TTP promoting subsequent increased release of cytokines upon pyroptosis. Further, we observe significantly increased levels of TTP expression in patients with inflammatory bowel disease (IBD), a disease for which altered cytokine expression is a key driver of pathogenesis. Inflammasome activation thus rapidly inactivates a pathway designed to suppress cytokine release, exacerbating hyperinflammatory states including those involved in autoinflammatory disease.