Mesenchymal Stem Cells Attenuate NADPH Oxidase-Dependent High Mobility Group Box 1 Production and Inhibit Abdominal Aortic Aneurysms

Arterioscler Thromb Vasc Biol. 2016 May;36(5):908-18. doi: 10.1161/ATVBAHA.116.307373. Epub 2016 Mar 17.

Abstract

Objective: Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, smooth muscle activation, and matrix degradation. This study tests the hypothesis that macrophage-produced high mobility group box 1 (HMGB1) production is dependent on nicotinamide adenine dinucleotide phosphate oxidase (Nox2), which leads to increase in interleukin (IL)-17 production resulting in AAA formation and that treatment with human mesenchymal stem cells (MSCs) can attenuate this process thereby inhibiting AAA formation.

Approach and results: Human aortic tissue demonstrated a significant increase in HMGB1 expression in AAA patients when compared with controls. An elastase-perfusion model of AAA demonstrated a significant increase in HMGB1 production in C57BL/6 (wild-type [WT]) mice, which was attenuated by MSC treatment. Furthermore, anti-HMGB1 antibody treatment of WT mice attenuated AAA formation, IL-17 production, and immune cell infiltration when compared with elastase-perfused WT mice on day 14. Elastase-perfused Nox2(-/y) mice demonstrated a significant attenuation of HMGB1 and IL-17 production, cellular infiltration, matrix metalloproteinase activity, and AAA formation when compared with WT mice on day 14. In vitro studies showed that elastase-treated macrophages from WT mice, but not from Nox2(-/y) mice, produced HMGB1, which was attenuated by MSC treatment. The production of macrophage-dependent HMGB1 involved Nox2 activation and superoxide anion production, which was mitigated by MSC treatment.

Conclusions: These results demonstrate that macrophage-produced HMGB1 leads to aortic inflammation and acts as a trigger for CD4(+) T-cell-produced IL-17 during AAA formation. HMGB1 release is dependent on Nox2 activation, which can be inhibited by MSCs leading to attenuation of proinflammatory cytokines, especially IL-17, and protection against AAA formation.

Keywords: HMGB1 protein; aortic aneurysms, abdominal; inflammation; interleukins; stem cells.

Publication types

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

MeSH terms

  • Animals
  • Aorta, Abdominal / enzymology*
  • Aorta, Abdominal / pathology
  • Aortic Aneurysm, Abdominal / enzymology
  • Aortic Aneurysm, Abdominal / genetics
  • Aortic Aneurysm, Abdominal / pathology
  • Aortic Aneurysm, Abdominal / prevention & control*
  • CD4-Positive T-Lymphocytes / metabolism
  • Case-Control Studies
  • Dilatation, Pathologic
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • HMGB1 Protein / metabolism*
  • Humans
  • Inflammation Mediators / metabolism
  • Interleukin-17 / metabolism
  • Lymphocyte Activation
  • Macrophage Activation
  • Macrophages / enzymology*
  • Male
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mesenchymal Stem Cell Transplantation*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NADPH Oxidase 2
  • NADPH Oxidases / deficiency
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism*
  • Pancreatic Elastase
  • Phenotype
  • Signal Transduction
  • Time Factors
  • Tissue Culture Techniques

Substances

  • HMGB1 Protein
  • HMGB1 protein, human
  • HMGB1 protein, mouse
  • Inflammation Mediators
  • Interleukin-17
  • Membrane Glycoproteins
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases
  • Pancreatic Elastase