Activation of human macrophage sodium channels regulates RNA processing to increase expression of the DNA repair protein PPP1R10

Immunobiology. 2019 Jan;224(1):80-93. doi: 10.1016/j.imbio.2018.10.005. Epub 2018 Oct 24.


Prior work demonstrated that a splice variant of SCN5A, a voltage-gated sodium channel gene, acts as a cytoplasmic sensor for viral dsRNA in human macrophages. Expression of this channel also polarizes macrophages to an anti-inflammatory phenotype in vitro and in vivo. Here we utilized global expression analysis of splice variants to identify novel channel-dependent signaling mechanisms. Pharmacological activation of voltage-gated sodium channels in human macrophages, but not treatment with cytoplasmic poly I:C, was associated with splicing of a retained intron in transcripts of PPP1R10, a regulator of phosphatase activity and DNA repair. Microarray analysis also demonstrated expression of a novel sodium channel splice variant, human macrophage SCN10A, that contains a similar exon deletion as SCN5A. SCN10A localizes to cytoplasmic and nuclear vesicles in human macrophages. Simultaneous expression of human macrophage SCN5A and SCN10A was required to decrease expression of the retained intron and increase protein expression of PPP1R10. Channel activation also increased protein expression of the splicing factor EFTUD2, and knockdown of EFTUD2 prevented channel dependent splicing of the retained PPP1R10 intron. Knockdown of the SCN5A and SCN10A variants in human macrophages reduced the severity of dsDNA breaks induced by treatment with bleomycin and type 1 interferon. These results suggested that human macrophage SCN5A and SCN10A variants mediate an innate immune signaling pathway that limits DNA damage through increased expression of PPP1R10. The functional significance of this pathway is that it may prevent cytotoxicity during inflammatory responses.

Keywords: DNA repair; Innate immune signaling; PPP1R10; SCN10A; SCN5A.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cells, Cultured
  • DNA Repair / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Knockdown Techniques
  • Humans
  • Immunity, Innate
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Macrophages / physiology*
  • Microarray Analysis
  • NAV1.5 Voltage-Gated Sodium Channel / genetics
  • NAV1.5 Voltage-Gated Sodium Channel / metabolism*
  • NAV1.8 Voltage-Gated Sodium Channel / genetics
  • NAV1.8 Voltage-Gated Sodium Channel / metabolism*
  • Peptide Elongation Factors / genetics
  • Peptide Elongation Factors / metabolism*
  • RNA Processing, Post-Transcriptional
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Ribonucleoprotein, U5 Small Nuclear / genetics
  • Ribonucleoprotein, U5 Small Nuclear / metabolism*
  • Signal Transduction
  • Up-Regulation


  • DNA-Binding Proteins
  • EFTUD2 protein, human
  • NAV1.5 Voltage-Gated Sodium Channel
  • NAV1.8 Voltage-Gated Sodium Channel
  • PPP1R10 protein, human
  • Peptide Elongation Factors
  • RNA-Binding Proteins
  • Ribonucleoprotein, U5 Small Nuclear
  • SCN10A protein, human
  • SCN5A protein, human