Related Experiment Video
Updated: Jun 24, 2025
Author Spotlight: THP-1 Macrophage Response to LPS/ATP — Unveiling the Pyroptosis, Apoptosis, and Necroptosis Spectrum
Published on: May 3, 2024
NLRP3 promotes radiation-induced brain injury by regulating microglial pyroptosis
Wan Zhang1, Qiheng Wu2, Xiaonan Zhang3
1Department of Radiation Oncology, The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, China.
Purpose:
Radiation-induced brain injury, one of the side effects of cranial radiotherapy in tumour patients, usually results in durable and serious cognitive disorders. Microglia are important innate immune-effector cells in the central nervous system. However, the interaction between microglia and neurons in radiation-induced brain injury remains uncharacterised.
Methods And Materials:
We established a microglia-neuron indirect co-culture model to assess the interaction between them. Microglia exposed to radiation were examined for pyroptosis using lactate dehydrogenase (LDH) release, Annexin V/PI staining, SYTOX staining and western blot. The role of nucleotide-binding oligomerisation domain-like receptor family pyrin domain containing 3 (NLRP3) was investigated in microglia exposed to radiation and in mouse radiation brain injury model through siRNA or inhibitor. Mini-mental state examination and cytokines in blood were performed in 23 patients who had experienced cranial irradiation.
Results:
Microglia exerted neurotoxic features after radiation in the co-culture model. NLRP3 was up-regulated in microglia exposed to radiation, and then caspase-1 was activated. Thus, the gasdermin D protein was cleaved, and it triggered pyroptosis in microglia, which released inflammatory cytokines. Meanwhile, treatment with siRNA NLRP3 in vitro and NLRP3 inhibitor in vivo attenuated the damaged neuron cell and cognitive impairment, respectively. What is more, we found that the patients after radiation with higher IL-6 were observed to have a decreased MMSE score.
Conclusions:
These findings indicate that radiation-induced pyroptosis in microglia may promote radiation-induced brain injury via the secretion of neurotoxic cytokines. NLRP3 was evaluated as an important mediator in radiation-induced pyroptosis and a promising therapeutic target for radiation-induced brain injury.
Insights
Radiation exposure triggers pyroptosis in microglia, leading to brain injury and cognitive decline. Targeting NLRP3 inflammasome offers a potential therapeutic strategy for mitigating these effects.
Area of Science:
- Neuroscience
- Immunology
- Oncology
Background:
- Cranial radiotherapy can cause lasting cognitive deficits due to radiation-induced brain injury.
- Microglia, the resident immune cells of the brain, play a crucial role in neuroinflammation.
- The specific interactions between microglia and neurons in the context of radiation injury are not fully understood.
Purpose of the Study:
- To investigate the role of microglia in radiation-induced brain injury.
- To elucidate the mechanism of microglial pyroptosis following radiation exposure.
- To evaluate the therapeutic potential of targeting the NLRP3 inflammasome pathway.
Main Methods:
- Established a microglia-neuron indirect co-culture model to study their interaction.
- Assessed microglial pyroptosis using LDH release, Annexin V/PI, SYTOX staining, and Western blot.
- Investigated the NLRP3 inflammasome pathway using siRNA and inhibitors in vitro and in vivo models.
- Evaluated cognitive function and cytokine levels in patients who underwent cranial irradiation.
Main Results:
- Radiation induced neurotoxic effects in microglia, characterized by pyroptosis and inflammatory cytokine release.
- NLRP3 inflammasome activation was identified as a key driver of radiation-induced microglial pyroptosis.
- Inhibition of NLRP3 inflammasome attenuated neuronal damage and cognitive impairment in preclinical models.
- Elevated IL-6 levels correlated with decreased cognitive scores (MMSE) in patients post-irradiation.
Conclusions:
- Radiation-induced pyroptosis in microglia contributes to brain injury and cognitive dysfunction through cytokine secretion.
- The NLRP3 inflammasome is a critical mediator of radiation-induced pyroptosis.
- Targeting the NLRP3 inflammasome presents a promising therapeutic avenue for managing radiation-induced brain injury.
