TPL2 kinase activity regulates microglial inflammatory responses and promotes neurodegeneration in tauopathy mice

Abstract

TPL2 (MAP3K8) is a central signaling node in the inflammatory response of peripheral immune cells. We find that TPL2 kinase activity modulates microglial cytokine release and is required for microglia-mediated neuron deathin vitro. In acutein vivoneuroinflammation settings, TPL2 kinase activity regulates microglia activation states and brain cytokine levels. In a tauopathy model of chronic neurodegeneration, loss of TPL2 kinase activity reduces neuroinflammation and rescues synapse loss, brain volume loss, and behavioral deficits. Single-cell RNAseq analysis indicates protection in the tauopathy model was associated with reductions in activated microglia subpopulations as well as infiltrating peripheral immune cells. Overall, using various models, we find that TPL2 kinase activity can promote multiple harmful consequences of microglial activation in the brain including cytokine release, iNOS induction, astrocyte activation, and immune cell infiltration. Consequently, inhibiting TPL2 kinase activity could represent a potential therapeutic strategy in neurodegenerative conditions.

Clusterin attenuates blood–brain barrier damage and cognitive impairment by inhibiting astrocyte aging in mice with sepsis-associated encephalopathy

“…When astrocytes are attacked, however, they release inflammatory mediators and cytokines (iNOS, ROS, etc. ), which are harmful to neurological function [13][14][15]. Previous studies have reported that activated astrocytes from multiple regions in the brain have a negative effect on synapse formation and neuronal function, which may lead to neurodegenerative disorders [16].…”