NOD2 regulates microglial inflammation through the TAK1-NF-κB pathway and autophagy activation in murine pneumococcal meningitis.

Abstract

Streptococcus pneumoniae is responsible for pneumococcal meningitis, with significant mortality and morbidity worldwide. Microglial inflammation plays a vital role in meningitis. The peptidoglycan sensor NOD2 (nucleotide-binding oligomerization domain 2) has been identified to promote microglia activation, but the role in autophagy following pneumococcal meningitis remains unclear. In the present study, we investigated the role of NOD2 in microglial inflammation and autophagy, as well as related signaling pathways, during S. pneumonia infection. NOD2 expression was knocked down by the injection of lentivirus-mediated short-hairpin RNA (shRNA). Our results revealed that NOD2 promotes microglial inflammation by increasing inflammatory mediators. We also showed that the TAK1-NF-κB pathway is involved in this process. In addition, NOD2 increased the expression of autophagy-related proteins and induced autophagosome formation. Rapamycin and 3-MA were utilized to assess the role of autophagy in microglial inflammation induced by S. pneumonia. We demonstrated that autophagy serves as a cellular defense mechanism to reduce inflammatory mediators. Similar to the in vitro results, NOD2 induced inflammation and autophagy in the brain in a mouse meningitis model. Moreover, NOD2 silencing significantly reduced brain edema and improved the neurological function of pneumococcal meningitis mice. Taken together, these data demonstrate that NOD2 promotes microglial inflammation and autophagy in murine pneumococcal meningitis, and the TAK1-NF-κB pathway is involved in microglial activation.

• Authors: Guan Wang, Yanan Fu, Kun Ma, Junli Liu, Xinjie Liu
• Journal: Brain research bulletin (Brain Res Bull) Vol. 158 Pg. 20-30 (05 2020) ISSN: 1873-2747 [Electronic] United States
• PMID: 32109527 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020. Published by Elsevier Inc.

Chemical References

• NF-kappa B
• Nod2 Signaling Adaptor Protein
• Nod2 protein, mouse
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Animals
• Autophagy (physiology)
• Cell Line
• Inflammation (metabolism, pathology)
• MAP Kinase Kinase Kinases (metabolism)
• Male
• Meningitis, Pneumococcal (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Microglia (metabolism, pathology)
• NF-kappa B (metabolism)
• Nod2 Signaling Adaptor Protein (antagonists & inhibitors, biosynthesis, deficiency)
• Signal Transduction (physiology)