The CD137L-CD137 axis is a potent co-stimulatory immune checkpoint regulator that forms a bidirectional signaling pathway between the CD137 ligand (CD137L) and CD137 receptor to regulate immunological activities. This study investigated the potential involvement of the CD137L-CD137 axis on inflammasome-associated brain injury and neurological deficits in a mouse model of focal ischemic stroke. Cerebral ischemia was induced in male C57BL/6J wild-type (WT), CD137L-deficient (CD137L KO) and CD137-deficient (CD137 KO) mice by middle cerebral artery occlusion (MCAO; 60 min), followed by reperfusion (6 h and 24 h). Brain infarct volume and neurological deficit scores were significantly lower in both CD137L KO and CD137 KO mice compared to WT controls. Moreover, CD137L-deficient brains had significantly lower levels of the pyroptotic protein, NT-Gasdermin D, while CD137-deficient brains had significantly lower levels of the pro-apoptotic proteins, cleaved caspase-3, pyroptotic protein, NT-Gasdermin D, and of the secondary pyroptotic protein NT-Gasdermin E, following ischemic stroke. This protection by CD137L and CD137 deletion was associated with a significant decrease in inflammasome signaling. In conclusion, our data provide evidence for the first time that the CD137L-CD137 axis contributes to brain injury and neurological deficits by activating the inflammasome signaling pathway following ischemic stroke.

CD137L-CD137 轴是一种有效的共刺激免疫检查点调节剂，在 CD137 配体 (CD137L) 和 CD137 受体之间形成双向信号通路以调节免疫活性。本研究调查了 CD137L-CD137 轴对局灶性缺血性中风小鼠模型中炎症小体相关脑损伤和神经功能缺损的潜在影响。通过大脑中动脉闭塞（MCAO；60 分钟）在雄性 C57BL/6J 野生型（WT）、CD137L 缺陷型（CD137L KO）和 CD137 缺陷型（CD137 KO）小鼠中诱导脑缺血，然后再灌注（6 小时）和 24 小时）。与 WT 对照相比，CD137L KO 和 CD137 KO 小鼠的脑梗塞体积和神经功能缺损评分显着降低。此外，CD137L 缺陷的大脑的焦亡蛋白水平显着降低，NT-Gasdermin D，而 CD137 缺陷的大脑在缺血性中风后的促凋亡蛋白、裂解的 caspase-3、焦亡蛋白 NT-Gasdermin D 和次级焦亡蛋白 NT-Gasdermin E 的水平显着降低。CD137L 和 CD137 缺失的这种保护与炎症小体信号传导的显着减少有关。总之，我们的数据首次提供证据表明 CD137L-CD137 轴通过激活缺血性中风后的炎症小体信号通路导致脑损伤和神经功能缺损。CD137L 和 CD137 缺失的这种保护与炎症小体信号传导的显着减少有关。总之，我们的数据首次提供证据表明 CD137L-CD137 轴通过激活缺血性中风后的炎症小体信号通路导致脑损伤和神经功能缺损。CD137L 和 CD137 缺失的这种保护与炎症小体信号传导的显着减少有关。总之，我们的数据首次提供证据表明 CD137L-CD137 轴通过激活缺血性中风后的炎症小体信号通路导致脑损伤和神经功能缺损。