1. Academic Validation
  2. NOD2-RIP2 signaling alleviates microglial ROS damage and pyroptosis via ULK1-mediated autophagy during Streptococcus pneumonia infection

NOD2-RIP2 signaling alleviates microglial ROS damage and pyroptosis via ULK1-mediated autophagy during Streptococcus pneumonia infection

  • Neurosci Lett. 2022 Jul 13;783:136743. doi: 10.1016/j.neulet.2022.136743.
Guan Wang 1 Chen Zhang 2 Fang Jiang 1 Mei Zhao 3 Shaohua Xie 4 Xinjie Liu 5
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Department of Pediatrics, Qilu Hospital of Shandong University, No.107 West Wenhua Road, Jinan 250012, Shandong Province, China.
  • 3 Department of Pediatrics, Shandong Maternal and Child Health Hospital, No.238 East Jingshi Road, Jinan 250000, Shandong Province, China.
  • 4 Department of Pediatrics, Liaocheng People's Hospital, No.67 West Dongchang Road, Liaocheng 252000, Shandong Province, China.
  • 5 Department of Pediatrics, Qilu Hospital of Shandong University, No.107 West Wenhua Road, Jinan 250012, Shandong Province, China. Electronic address: [email protected].
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.

Keywords

Autophagy; Microglia; NOD2; Pyroptosis; RIP2; ULK1.

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