Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling

Abstract

Astrocyte activation is a common feature of neurodegenerative diseases. However, the ways in which dying neurons influence the activity of astrocytes is poorly understood. RIPK3 signaling has recently been described as a key regulator of neuroinflammation, but whether this kinase mediates astrocytic responsiveness to neuronal death has not yet been studied. Here, we used the MPTP model of Parkinson′s disease to show that activation of astrocytic RIPK3 drives dopaminergic cell death and axon damage. Transcriptomic profiling revealed that astrocytic RIPK3 promoted gene expression associated with neuroinflammation and movement disorders, and this coincided with significant engagement of DAMP signaling. Using human cell culture systems, we show that factors released from dying neurons signal through RAGE to induce RIPK3-dependent astrocyte activation. These findings highlight a mechanism of neuron-glia crosstalk in which neuronal death perpetuates further neurodegeneration by engaging inflammatory astrocyte activation via RIPK3.

Die hard: necroptosis and its impact on age-dependent neuroinflammatory diseases

“…Activated RIPK3 induces transcription of genes encoding inflammatory cytokines and chemokines, causing an increase in the translation of these mediators, which continues even once cell membrane integrity has been compromised (Orozco et al, 2019). Factors released due to necroptosis activate nearby astrocytes, increasing RIPK3 transcription and signaling, causing an increase in pro-inflammatory cytokine production and release (Chang et al, 2023). Activation of RIPK1 in both microglia and astrocytes can also induce the production of pro-inflammatory cytokines via the activation of Nuclear Factor-kB (NF-κB) in the absence of active caspases (Huang et al, 2021;Zelic et al, 2021).…”

“…However, with chronic exposure to DAMPs and activation, microglia will remain in the pro-inflammatory M1-like phenotype and do more harm than good (Cherry et al, 2014). Interestingly, DAMPs and other factors released as a by-product of necroptosis activate astrocytes, increasing astrocytic RIPK3 transcription and signaling, further driving inflammatory transcription and neurotoxicity (Figure 1) (Chang et al, 2023). Therefore, necroptosis activates the proinflammatory states of both microglia and astrocytes in the brain.…”