Behavioral Changes in Mice Lacking Interleukin-33

eNeuro. 2017 Dec 26;4(6):ENEURO.0147-17.2017. doi: 10.1523/ENEURO.0147-17.2017. eCollection 2017 Nov-Dec.


Interleukin (IL)-33 is a member of the IL-1 family of cytokines. IL-33 is expressed in nuclei and secreted as alarmin upon cellular damage to deliver a danger signal to the surrounding cells. Previous studies showed that IL-33 is expressed in the brain and that it is involved in neuroinflammatory and neurodegenerative processes in both humans and rodents. Nevertheless, the role of IL-33 in physiological brain function and behavior remains unclear. Here, we have investigated the behaviors of mice lacking IL-33 (Il33-/- mice). IL-33 is constitutively expressed throughout the adult mouse brain, mainly in oligodendrocyte-lineage cells and astrocytes. Notably, Il33-/- mice exhibited reduced anxiety-like behaviors in the elevated plus maze (EPM) and the open field test (OFT), as well as deficits in social novelty recognition, despite their intact sociability, in the three-chamber social interaction test. The immunoreactivity of c-Fos proteins, an indicator of neuronal activity, was altered in several brain regions implicated in anxiety-related behaviors, such as the medial prefrontal cortex (mPFC), amygdala, and piriform cortex (PCX), in Il33-/- mice after the EPM. Altered c-Fos immunoreactivity in Il33-/- mice was not correlated with IL-33 expression in wild-type (WT) mice nor was IL-33 expression affected by the EPM in WT mice. Thus, our study has revealed that Il33-/- mice exhibit multiple behavioral deficits, such as reduced anxiety and impaired social recognition. Our findings also indicate that IL-33 may regulate the development and/or maturation of neuronal circuits, rather than control neuronal activities in adult brains.

Keywords: IL-33; anxiety; astrocytes; cytokines; oligodendrocytes; social behavior.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / metabolism
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Behavior, Animal / physiology*
  • Brain / metabolism
  • Brain / pathology
  • Interleukin-33 / deficiency*
  • Interleukin-33 / genetics
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout / metabolism
  • Mice, Knockout / psychology*
  • Neurons / metabolism
  • Neurons / pathology
  • Oligodendroglia / metabolism
  • Oligodendroglia / pathology
  • Proto-Oncogene Proteins c-fos / metabolism
  • Recognition, Psychology / physiology


  • Il33 protein, mouse
  • Interleukin-33
  • Proto-Oncogene Proteins c-fos