Thrombopoietin mitigates neuronal death by enhancing mitophagy and suppressing NLRP3 inflammasome activation under oxygen-glucose deprivation conditions.

Abstract

Thrombopoietin (TPO), a principal hematopoietic cytokine, regulates the development and proliferation of megakaryocytes and platelets. Our previous research demonstrated TPO's neuroprotective role against hypoxic-ischemic brain injury in rats. Yet, the underlying mechanisms remain unclear. This study reveals that A20 [tumor necrosis factor alpha (TNF-α)-induced protein 3 (Tnfaip3)] significantly contributes to TPO's neuroprotective effect by enhancing mitophagy in neurons. TPO reduces cell death under oxygen-glucose deprivation (OGD) conditions. Mechanistically, TPO induces the TNF-α and NF-κB signaling pathways to increase A20 expression, thereby promoting mitophagy, diminishing reactive oxygen species (ROS) production, and stabilizing mitochondrial membrane potential (MMP). A20 maintains mitochondrial dynamics and mitigates OGD-induced excessive mitochondrial fission. Furthermore, A20 suppresses NLRP3 inflammasome activation by enhancing mitophagy. This study elucidates a novel mechanism of TPO's neuroprotection, distinct from its hematological effects, supporting its potential therapeutic application in treating neurological injuries.NEW & NOTEWORTHY TPO, known for its role in megakaryocytes development and platelets production, also protects neurons from damage caused by oxygen and glucose deprivation. Thrombopoietin (TPO) boosts the A20 protein, which enhances the cell's mitophagy for damaged mitochondria. This reduces harmful reactive oxygen species (ROS) and inflammation, ultimately promoting neuron survival. This discovery opens new avenues for using TPO to treat neurological injuries.