RNF11 modulates microglia activation through NF-κB signalling cascade

Neurosci Lett. 2012 Oct 24;528(2):174-9. doi: 10.1016/j.neulet.2012.08.060. Epub 2012 Sep 11.

Abstract

Microglia are resident macrophages in the central nervous system (CNS) that play a major role in neuroinflammation and pathogenesis of several neurodegenerative diseases. Upon activation, microglia releases a multitude of pro-inflammatory factors that initiate and sustain an inflammatory response by activating various signalling pathways, including the NF-κB pathway in a feed forward cycle. In microglial cells, activation of NF-κB signalling is normally transient, while sustained NF-κB activation is associated with persistent neuroinflammation. RING finger protein 11 (RNF11), in association with A20 ubiquitin-editing complex, is one of the key negative regulators of NF-κB signalling pathway in neurons. In this study, we have demonstrated and confirmed this role of RNF11 in microglia, the immune cells of the CNS. Coimmunoprecipitation experiments showed that RNF11 and A20 interact in a microglial cell line, suggesting the presence of A20 ubiquitin-editing protein complex in microglial cells. Next, using targeted short hairpin RNA (shRNA) knockdown and over-expression of RNF11, we established that RNF11 expression levels are inversely related to NF-κB activation, as evident from altered expression of NF-κB transcribed genes. Moreover our studies, illustrated that RNF11 confers protection against LPS-induced cell cytotoxicity. Thus our investigations clearly demonstrated that microglial RNF11 is a negative regulator of NF-κB signalling pathway and could be a strong potential target for modulating inflammatory responses in neurodegenerative diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Survival
  • Cells, Cultured
  • Cysteine Endopeptidases
  • DNA-Binding Proteins / metabolism
  • Humans
  • Inflammation / immunology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipopolysaccharides / pharmacology
  • Mice
  • Microglia / cytology
  • Microglia / immunology
  • Microglia / physiology*
  • NF-kappa B / physiology*
  • Neuroimmunomodulation
  • Primary Cell Culture
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • RNA, Messenger
  • RNF11 protein, human
  • Rnf11 protein, mouse
  • Ubiquitin-Protein Ligases
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Cysteine Endopeptidases
  • Tnfaip3 protein, mouse