Abstract
Radiation-induced brain injury (RI) commonly occurs in patients who received head and neck radiotherapy. However, the mechanism of RI remains unclear. We aimed to evaluate whether pyroptosis was involved in RI and the impact of mesenchymal stem cells (MSCs) on it. BALB/c male mice (6–8 weeks) were cranially irradiated (15 Gy), and MSCs were transplanted into the bilateral cortex 2 days later; then mice were sacrificed 1 month later. Meanwhile, irradiated BV-2 microglia cells (10 Gy) were cocultured with MSCs for 24 hours. We observed that irradiated mice brains presented NLRP3 and caspase-1 activation. RT-PCR then indicated that it mainly occurred in microglia cells but not in neurons. Further, irradiated BV-2 cells showed pyroptosis and increased production of IL-18 and IL-1β. RT-PCR also demonstrated an increased expression of several inflammasome genes in irradiated BV-2 cells, including NLRP3 and AIM2. Particularly, NLRP3 was activated. Knockdown of NLRP3 resulted in decreased LDH release. Noteworthily, in vivo, MSCs transplantation alleviated radiation-induced NLRP3 and caspase-1 activation. Moreover, in vitro, MSCs could decrease caspase-1 dependent pyroptosis, NLRP3 inflammasome activation, and ROS production induced by radiation. Thus, our findings proved that microglia pyroptosis occurred in RI. MSCs may act as a potent therapeutic tool in attenuating pyroptosis.
Highlights
IntroductionSeveral theories have been proposed to explain the development of radiation-induced brain injury, including direct injury from radiation [8,9,10], damage on cerebral vascular system [11, 12], immunoinflammatory responses [13], and oxidative stress [14]
Radiotherapy is commonly used in patients with head and neck cancer [1]
To determine whether increased NLRP3 and caspase-1 expression is present in radiationinduced brain injury, we examined the cortices from the mice that had received 15 Gy irradiation
Summary
Several theories have been proposed to explain the development of radiation-induced brain injury, including direct injury from radiation [8,9,10], damage on cerebral vascular system [11, 12], immunoinflammatory responses [13], and oxidative stress [14]. Pyroptosis, a regulated cell death, is dependent on caspase-1 activation, which eventually causes the loss of plasma membrane integrity [15,16,17] as well as promoting inflammatory response [18]. Previous studies found that the development of pyroptosis has a close relationship with the activation of inflammasomes [16]. Recent studies indicate that caspase-1 and inflammasomes expression were significantly upregulated in the lung tissue and oral mucosa after radiation [19, 20]. Whether pyroptosis occurs in radiation-induced brain injury is still unclear
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