C/EBPβ deficiency enhances the keratinocyte innate immune response to direct activators of cytosolic pattern recognition receptors

Innate Immun. 2023 Jan;29(1-2):14-24. doi: 10.1177/17534259231162192. Epub 2023 Apr 24.


The skin is the first line of defense to cutaneous microbes and viruses, and epidermal keratinocytes play a critical role in preventing infection by viruses and pathogens through activation of the type I interferon (IFN) response. Using RNAseq analysis, here we report that the conditional deletion of C/EBPβ transcription factor in mouse epidermis (CKOβ mice) resulted in the upregulation of IFNβ and numerous keratinocyte interferon-stimulated genes (ISGs). The expression of cytosolic pattern recognition receptors (cPRRs), that recognize viral RNA and DNA, were significantly increased, and enriched in the RNAseq data set. cPRRs stimulate a type I IFN response that can trigger cell death to eliminate infected cells. To determine if the observed increases in cPRRs had functional consequences, we transfected CKOβ primary keratinocytes with the pathogen and viral mimics poly(I:C) (dsRNA) or poly(dA:dT) (synthetic B-DNA) that directly activate PRRs. Transfected CKOβ primary keratinocytes displayed an amplified type I IFN response which was accompanied by increased activation of IRF3, enhanced ISG expression, enhanced activation of caspase-8, caspase-3 and increased apoptosis. Our results identify C/EBPβ as a critical repressor of the keratinocyte type I IFN response, and demonstrates that the loss of C/EBPβ primes keratinocytes to the activation of cytosolic PRRs by pathogen RNA and DNA to induce cell death mediated by caspase-8 and caspase-3.

Keywords: C/EBPβ; cell death; keratinocytes; type I IFN response.

Publication types

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

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-beta* / genetics
  • Caspase 3 / metabolism
  • Caspase 8 / metabolism
  • Immunity, Innate
  • Interferon Type I* / metabolism
  • Keratinocytes
  • Mice
  • Receptors, Pattern Recognition / genetics
  • Receptors, Pattern Recognition / metabolism


  • Caspase 3
  • Caspase 8
  • CCAAT-Enhancer-Binding Protein-beta
  • Interferon Type I
  • Receptors, Pattern Recognition
  • Cebpb protein, mouse