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Ectodomain Shedding by ADAM17 Increases the Release of Soluble CD40 from Human Endothelial Cells under

Anton Klersy1, Sören Meyer2, Florian Leuschner2

  • 1Department of Cardiovascular Physiology, Heidelberg University, 69120 Heidelberg, Germany.

Cells
|August 11, 2023
PubMed

Insights

Homozygosity for the CD40 gene C allele links to coronary heart disease (CHD). ADAM17 enzyme sheds CD40, increasing soluble CD40 (sCD40), a potential CHD biomarker.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cardiovascular Research

Background:

  • The CD40 gene's -1T>C polymorphism (rs1883832), specifically the CC genotype, is linked to coronary heart disease (CHD) susceptibility.
  • This genotype is associated with increased CD40 expression and shedding on cell surfaces.
  • The enzyme ADAM17 is known to cleave various cell surface proteins.

Purpose of the Study:

  • To investigate the association between ADAM17-mediated CD40 shedding and inflammation.
  • To examine the role of ADAM17 in CD40 shedding in human endothelial cells with the CC genotype.

Main Methods:

  • Human umbilical vein endothelial cells (HUVEC) with the CC genotype were stimulated with soluble CD40 ligand (sCD40L) or tumor necrosis factor-α (TNFα).
  • Messenger RNA and protein expression levels were analyzed using standard molecular biology techniques.
  • Plasma levels of soluble CD40 (sCD40), high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6) were measured using ELISA in patients with CHD.

Main Results:

  • ADAM17 and its regulator iRhom2 surface abundance increased upon stimulation with CD40L and TNFα.
  • Inhibiting ADAM17 reduced TNFα-induced release of sCD40 and soluble vascular cell adhesion molecule-1, while increasing surface CD40.
  • ADAM17 inhibition led to upregulated monocyte chemoattractant protein-1 (MCP-1) mRNA and protein following CD40L or TNFα stimulation.
  • Plasma sCD40 levels positively correlated with inflammatory biomarkers hs-CRP and IL-6 in CHD patients.

Conclusions:

  • A mechanism is proposed where ADAM17 sheds membrane-bound CD40 from endothelial cells, increasing soluble CD40 (sCD40) levels.
  • This shedding process may limit downstream CD40 signaling.
  • Soluble CD40, particularly in individuals with the CC genotype of the CD40 gene, may serve as a significant biomarker for coronary heart disease.
Abstract

Keywords:
ADAM17biomarkerendothelial cellssingle nucleotide polymorphismsoluble CD40

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