YAP Regulates Microglial Anti-Inflammatory Responses and Alleviates Cognitive Impairment Through the IL-33/ST2...

Area of Science:

• Neuroscience
• Cell Biology
• Immunology

Background:

• Traumatic brain injury (TBI) is a significant cause of mortality and morbidity.
• Neuroinflammation and microglial responses are critical factors influencing TBI outcomes.
• Interleukin-33 (IL-33) and Yes-associated protein (YAP) have been implicated in TBI pathogenesis and prognosis.

Purpose of the Study:

• To investigate the role of astrocyte-derived YAP in regulating IL-33 production and its impact on neuroinflammation and cognitive function after TBI.
• To elucidate the signaling pathway involving YAP, IL-33, and ST2 receptors in the context of TBI.

Main Methods:

• Assessed microglial inflammatory markers in vivo and in vitro.
• Overexpressed YAP in astrocytes using viral vectors (AAV and lentivirus).
• Evaluated protein expression via Western blotting and immunofluorescence, and gene regulation using ChIP-qPCR.
• Blocked IL-33/ST2 signaling with astegolimab.
• Assessed cognitive function using Morris water maze and Y-maze tests.

Main Results:

• YAP and IL-33 levels were decreased in the early phase of TBI, along with reduced anti-inflammatory markers (CD206) in microglia.
• YAP directly binds to the IL33 promoter, enhancing IL-33 secretion and activating the IL-33/ST2 pathway.
• Activation of this pathway promoted microglial anti-inflammatory responses via NF-κB signaling, improving cognitive function.
• Blocking ST2 receptors with astegolimab reversed the beneficial effects, confirming the mechanism's specificity.

Conclusions:

• Astrocyte-derived YAP plays a protective role in TBI by upregulating IL-33.
• The YAP/IL-33/ST2 signaling axis modulates microglial anti-inflammatory responses, leading to improved cognitive outcomes after TBI.
• Targeting the YAP/IL-33/ST2 pathway represents a potential therapeutic strategy for TBI treatment.