TRPV4 exacerbates neurological deficits after traumatic brain injury through the Ca2+-ROS-pyroptosis signaling axis.

OBJECTIVE

Calcium (Ca2+) overload is a critical driver of secondary injury following traumatic brain injury (TBI). The transient receptor potential vanilloid 4 (TRPV4), a Ca2+-permeable cation channel pivotal in calcium signaling, may contribute to post-traumatic Ca2+ dysregulation and neuronal damage. This study aimed to elucidate the role of TRPV4 in TBI pathogenesis and its potential mechanism.

METHODS

To explore this, we established an in vivo TBI model using controlled cortical impact (CCI) and an in vitro model by mechanically scratching HT22 neuronal cells. TRPV4 expression was modulated through lentivirus infection and adeno-associated virus injection. Subsequently, a series of in vivo and in vitro experiments were conducted to evaluate TRPV4's effect.

RESULTS

The expression of TRPV4 was significantly upregulated in neurons following TBI. TRPV4 overexpression markedly increased lesion volume, neurological deficits, and neuronal loss, whereas TRPV4 knockdown mitigated these effects. Furthermore, TRPV4 activation disrupted mitochondrial dynamics and function, promoting neuronal pyroptosis. Mechanistically, TRPV4-mediated Ca2+ influx amplified reactive oxygen species (ROS) production and NF-κB phosphorylation, exacerbating mitochondrial damage and activating pyroptotic signaling pathways.

CONCLUSIONS

In conclusion, our findings demonstrate that elevated neuronal TRPV4 expression aggravates secondary brain injury following TBI through the TRPV4-Ca2+-ROS-pyroptosis signaling axis. These insights underscore TRPV4 as a promising therapeutic target for mitigating TBI-related damage.