Interleukin 1 type 1 receptor restore: a genetic mouse model for studying interleukin 1 receptor-mediated effects in specific cell types

J Neurosci. 2015 Feb 18;35(7):2860-70. doi: 10.1523/JNEUROSCI.3199-14.2015.


Interleukin-1 (IL-1) mediates diverse neurophysiological and neuropathological effects in the CNS through type I IL-1 receptor (IL-1R1). However, identification of IL-1R1-expressing cell types and cell-type-specific functions of IL-1R1 remains challenging. In this study, we created a novel genetic mouse model in which IL-1R1 gene expression is disrupted by an intronic insertion of a loxP flanked disruptive sequence that can be deleted by Cre recombinase, resulting in restored IL-1R1 gene expression under its endogenous promoters. A second mutation was introduced at stop codon of the IL-1R1 gene to allow tracking of the restored IL-1R1 protein by a 3HA tag and IL-1R1 mRNA by tdTomato fluorescence. These animals were designated as IL-1R1(r/r) and exhibited an IL-1R1 knock-out phenotype. We used IL-1R1 globally restored mice (IL-1R1(GR/GR)) as an IL-1R1 reporter and observed concordant labeling of IL-1R1 mRNA and protein in brain endothelial cells. Two cell-type-specific IL-1R1 restore lines were generated: Tie2Cre-IL-1R1(r/r) and LysMCre-IL-1R1(r/r). Brain endothelial COX-2 expression, CNS leukocyte infiltration, and global microglia activation induced by intracerebroventricular injection of IL-1β were not observed in IL-1R1(r/r) or LysMCre-IL-1R1(r/r) mice, but were restored in Tie2Cre-IL-1R1(r/r) mice. These results reveal IL-1R1 expression in endothelial cells alone is sufficient to mediate these central IL-1-induced responses. In addition, ex vivo IL-1β stimulation increased IL-1β expression in bone marrow cells in wild-type, Tie2Cre-IL-1R1(r/r), and LysMCre-IL-1R1(r/r), but not IL-1R1(r/r) mice. These results demonstrate this IL-1R1 restore model is a valuable tool for studying cell-type-specific functions of IL-1R1.

Keywords: blood–brain barrier; endothelial cells; interleukin 1; knock-in; neuroinflammation; restore.

Publication types

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

MeSH terms

  • Animals
  • Bone Marrow Cells / metabolism
  • Brain / cytology*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Embryo, Mammalian
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Genotype
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Interleukin-1beta / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism
  • Receptors, Interleukin-1 Type I / genetics*
  • Receptors, Interleukin-1 Type I / metabolism*
  • Time Factors


  • Aif1 protein, mouse
  • Calcium-Binding Proteins
  • Homeodomain Proteins
  • IL1R1 protein, mouse
  • Interleukin-1beta
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Receptors, Interleukin-1 Type I
  • engrailed 2 protein
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2