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Updated: May 5, 2026
Sub-acute Cerebral Microhemorrhages Induced by Lipopolysaccharide Injection in Rats
Published on: October 17, 2018
Microglial mitochondrial DNA release contributes to neuroinflammation after intracerebral hemorrhage through
Feng Gu1, Zongqi Wang1, Haojie Ding1
1Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China.
Abstract:
Intracerebral hemorrhage (ICH) is a severe disease that often leads to disability and death. Neuroinflammatory response is a key causative factor of early secondary brain injury after ICH. AIM2 is a DNA-sensing protein that recognizes cytosolic double-stranded DNA and take a significant part in neuroinflammation. Mitochondrial DNA participates in the translation of proteins such as the respiratory chain in the mitochondria. Whether mtDNA is involved in forming AIM2 inflammasome after ICH remains unclear. We used mice to construct ICH model in vivo and we used BV2 microglial cells treated with oxyhemoglobin to simulate ICH in vitro. Following lentiviral transfection to overexpress AIM2 antagonist P202, a notable decrease was observed in the levels of AIM2 inflammasome-associated proteins, leading to a reduction in dead neurons surrounding the hematoma and an enhancement in long-term and short-term behavior of neurological deficits. We further explored whether mtDNA took part in the AIM2 activation after ICH. The cytosolic mtDNA level was down-regulated by the mitochondrial division protector Mdivi-1 and up-regulated by transfection of mtDNA into cytoplasm. We found the expression level of AIM2 inflammasome-related proteins and inflammatory cytokines release were regulated by the cytosolic mtDNA level. In conclusion, after ICH, the mtDNA content in the cytoplasm of microglia around the hematoma rises, causing AIM2 inflammation leading to neuronal apoptosis, which leads to neurological deficits in mice. On the other hand, P202 was able to block inflammatory vesicle activation and improve neurological function by preventing the interaction between AIM2 protein and mitochondrial DNA.
Insights
Mitochondrial DNA in microglia cytoplasm activates AIM2 inflammasome, causing brain injury after intracerebral hemorrhage (ICH). Blocking this interaction with P202 reduces inflammation and improves neurological function in mice.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Intracerebral hemorrhage (ICH) is a severe condition leading to significant disability and death.
- Neuroinflammation is a critical factor in secondary brain injury following ICH.
- The AIM2 inflammasome, a DNA-sensing complex, plays a role in neuroinflammation.
Purpose of the Study:
- To investigate the role of mitochondrial DNA (mtDNA) in AIM2 inflammasome activation after ICH.
- To explore the therapeutic potential of targeting the AIM2-mtDNA interaction for neurological recovery.
Main Methods:
- An in vivo mouse model of ICH and an in vitro BV2 microglial cell model using oxyhemoglobin.
- Overexpression of an AIM2 antagonist (P202) via lentiviral transfection.
- Manipulation of cytosolic mtDNA levels using Mdivi-1 and mtDNA transfection.
Main Results:
- Overexpression of P202 decreased AIM2 inflammasome proteins, reduced neuronal death, and improved neurological function.
- Cytosolic mtDNA levels were found to regulate AIM2 inflammasome activation and inflammatory cytokine release.
- Increased cytosolic mtDNA in microglia around the hematoma correlated with AIM2 activation and neuronal apoptosis.
Conclusions:
- Elevated cytosolic mtDNA in microglia contributes to AIM2 inflammasome activation, leading to neuronal apoptosis and neurological deficits post-ICH.
- The AIM2 antagonist P202 mitigates ICH-induced brain injury by inhibiting the AIM2-mtDNA interaction, thereby improving neurological outcomes.
