{Reference Type}: Journal Article
{Title}: IL-17A exacerbates caspase-12-dependent neuronal apoptosis following ischemia through the Src-PLCγ-calpain pathway.
{Author}: Wang H;Han S;Xie J;Zhao R;Li S;Li J;
{Journal}: Exp Neurol
{Volume}: 379
{Issue}: 0
{Year}: 2024 Jun 11
{Factor}: 5.62
{DOI}: 10.1016/j.expneurol.2024.114863
{Abstract}: Interleukin-17 A (IL-17 A) contributes to inflammation and causes secondary injury in post-stroke patients. However, little is known regarding the mechanisms that IL-17 A is implicated in the processes of neuronal death during ischemia. In this study, the mouse models of middle cerebral artery occlusion/reperfusion (MCAO/R)-induced ischemic stroke and oxygen-glucose deprivation/reoxygenation (OGD/R)-simulated in vitro ischemia in neurons were employed to explore the role of IL-17 A in promoting neuronal apoptosis. Mechanistically, endoplasmic reticulum stress (ERS)-induced neuronal apoptosis was accelerated by IL-17 A activation through the caspase-12-dependent pathway. Blocking calpain or phospholipase Cγ (PLCγ) inhibited IL-17 A-mediated neuronal apoptosis under ERS by inhibiting caspase-12 cleavage. Src and IL-17 A are linked, and PLCγ directly binds to activated Src. This binding causes intracellular Ca2+ flux and activates the calpain-caspase-12 cascade in neurons. The neurological scores showed that intracerebroventricular (ICV) injection of an IL-17 A neutralizing mAb decreased the severity of I/R-induced brain injury and suppressed apoptosis in MCAO mice. Our findings reveal that IL-17 A increases caspase-12-mediated neuronal apoptosis, and IL-17 A suppression may have therapeutic potential for ischemic stroke.