IL-33/ST2L Signaling Provides Neuroprotection Through Inhibiting Autophagy, Endoplasmic Reticulum Stress, and...

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Interleukin-33 (IL-33) is an IL-1 family cytokine that binds to the IL-1 receptor ST2.
• The IL-33/ST2 axis is implicated in central nervous system (CNS) diseases and injury, including traumatic brain injury (TBI).
• The precise roles and mechanisms of the IL-33/ST2 axis in TBI pathogenesis are not fully understood.

Purpose of the Study:

• To investigate the role of IL-33/ST2 signaling in TBI-induced brain edema and neurobehavioral deficits in mice.
• To elucidate the underlying molecular mechanisms, including endoplasmic reticulum (ER) stress, apoptosis, autophagy, and neuroinflammation.

Main Methods:

• Investigated IL-33 and ST2L levels post-TBI using immunofluorescence.
• Administered IL-33 and salubrinal (SAL), an ER stress inhibitor, to TBI mouse models.
• Assessed brain edema, motor function, and spatial learning/memory.
• Analyzed levels of IL-1β, TNF-α, ER stress markers, apoptosis, and autophagy.
• Utilized anti-ST2L treatment to block IL-33/ST2 signaling.

Main Results:

• IL-33 levels increased, while ST2L levels decreased at 24 hours post-TBI.
• IL-33 treatment alleviated TBI-induced brain edema, motor deficits, and spatial memory impairments.
• IL-33 and SAL suppressed TBI-induced increases in IL-1β, TNF-α, ER stress, apoptosis, and autophagy.
• Anti-ST2L treatment reversed the protective effects of IL-33.

Conclusions:

• The IL-33/ST2 axis plays a protective role in mitigating TBI-induced brain edema and neurobehavioral deficits.
• IL-33/ST2 signaling exerts its effects by suppressing autophagy, ER stress, apoptosis, and neuroinflammation.
• Targeting the IL-33/ST2 pathway represents a potential therapeutic strategy for TBI.