CARD3 Promotes Cerebral Ischemia-Reperfusion Injury Via Activation of TAK1

Area of Science:

• Neuroscience
• Immunology
• Molecular Biology

Background:

• Stroke treatments lack significant clinical progress despite studying multiple signaling pathways.
• The role of Caspase Activation and Recruitment Domain 3 (CARD3) in cerebral stroke is currently unknown.
• CARD3 is involved in immunity, inflammation, lipid metabolism, and apoptosis.

Purpose of the Study:

• To investigate the role of CARD3 in the pathological process of cerebral ischemia-reperfusion (I-R) injury.
• To elucidate the underlying molecular mechanisms of CARD3's involvement in I-R injury.
• To explore CARD3 as a potential therapeutic target for stroke.

Main Methods:

• Utilized a mouse model of middle cerebral artery occlusion/reperfusion (MCAO) to induce I-R injury.
• Generated CARD3-knockout and neuron-specific CARD3-overexpressing transgenic mice.
• Analyzed inflammatory response, neuronal apoptosis, infarct volume, and neuropathological scores.
• Investigated the activation of TAK1 (transforming growth factor-β-activated kinase 1) pathway.
• Administered TAK1 inhibitor (5Z-7-oxozeaenol) to assess its therapeutic effect.

Main Results:

• CARD3 expression was upregulated in a time-dependent manner during I-R injury.
• CARD3-knockout mice showed reduced inflammation, neuronal apoptosis, infarct volume, and neuropathological scores.
• CARD3-overexpressing mice exhibited exacerbated I-R injury, increased TAK1 activation, inflammation, and apoptosis.
• TAK1 inhibition reversed the increased inflammation and apoptosis in CARD3-overexpressing mice.

Conclusions:

• CARD3 promotes I-R injury in the brain by activating the TAK1 pathway.
• This study reveals a novel regulatory axis (CARD3-TAK1) in I-R brain injury.
• Targeting CARD3 or TAK1 presents a potential therapeutic strategy for ischemic stroke.