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NOD2-RIP2 signaling alleviates microglial ROS damage and pyroptosis via ULK1-mediated autophagy during Streptococcus
Guan Wang1, Chen Zhang2, Fang Jiang1
1Department of Pediatrics, Qilu Hospital of Shandong University, No.107 West Wenhua Road, Jinan 250012, Shandong Province, China; NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No.44 West Wenhua Road, Jinan 250012, Shandong Province, China.
Abstract:
Meningitis occurs when S. pneumonia invade the blood-brain barrier, provoking inflammatory host response and neurological injury. Nucleotide-binding oligomerization domain 2 (NOD2) has been identified to promote microglial activation and autophagy during pneumococcal meningitis, but the mechanism remains unclear. In the present study, we investigated the passway of NOD2-mediated autophagy activation and the role of autophagy in inflammatory damage of murine microglia and mouse meningitis model. We demonstrated that autophagy was activated during S. pneumonia infection, and NOD2-RIP2 signaling was involved in the process. Treatment of microglia with GSK583, the RIP2 kinase inhibitor resulted in reduced autophagy-related protein and p-ULK1, indicating that RIP2 regulated autophagy in a kinase-dependent manner by phosphorylating ULK1. In addition, microglia with ULK1 knockdown exhibited enhanced production of ROS, leading to IL-1β and IL-18 release and cellular pyroptosis. Similar to the in vitro results, NOD2-RIP2 signaling induced autophagy in the brain in a mouse meningitis model. Moreover, ULK1 or RIP2 silencing significantly increased pyroptosis of brain and induced more inflammatory damage of pneumococcal meningitis mice. Taken together, our study demonstrate that NOD2-RIP2 signaling is involved in the activation of autophagy by promoting ULK1 phosphorylation, which alleviates microglial ROS damage and pyroptosis during S. pneumonia infection.
Insights
Nucleotide-binding oligomerization domain 2 (NOD2) signaling activates autophagy via ULK1 phosphorylation, reducing inflammation and pyroptosis in pneumococcal meningitis. This pathway protects against neurological injury during infection.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Pneumococcal meningitis causes inflammation and neurological damage.
- Nucleotide-binding oligomerization domain 2 (NOD2) influences microglial activation and autophagy, but its precise role is unclear.
Purpose of the Study:
- To investigate the mechanism of NOD2-mediated autophagy activation.
- To determine the role of autophagy in inflammatory damage during pneumococcal meningitis.
Main Methods:
- In vitro study using murine microglia and an in vivo mouse meningitis model.
- Utilized RIP2 kinase inhibitor (GSK583) and ULK1 knockdown.
- Analyzed autophagy-related proteins, p-ULK1, reactive oxygen species (ROS), IL-1β, IL-18, and pyroptosis.
Main Results:
- Autophagy is activated during S. pneumoniae infection, involving NOD2-RIP2 signaling.
- RIP2 kinase activity and ULK1 phosphorylation are crucial for autophagy regulation.
- ULK1 knockdown in microglia increased ROS, IL-1β, IL-18 release, and pyroptosis.
- NOD2-RIP2 signaling induced autophagy in the brain; ULK1 or RIP2 silencing worsened meningitis pathology and pyroptosis.
Conclusions:
- NOD2-RIP2 signaling activates autophagy by promoting ULK1 phosphorylation.
- This autophagy activation alleviates microglial ROS damage and pyroptosis.
- The NOD2-RIP2-ULK1 pathway is a key regulator of inflammation and neuronal injury in pneumococcal meningitis.
