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

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 box1 (HMGB1) production is dependent on NADPH oxidase (Nox2) which leads to increase in 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 compared to 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 compared to 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 compared to WT mice on day 14. In vitro studies showed that elastase-treated macrophages from WT mice, but not 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.

Reactive Oxygen Species Generation and Atherosclerosis

“…In addition to shear stress, growth factors and cytokines have been shown to directly regulate SMC differentiation, and the expression levels of cytokines and growth factors are likewise altered during differentiation of mesenchymal stem cells, for example. 117 Importantly, it was found that oxidative stress is essential for stem cells to differentiate into SMCs. 118 ROS are highly reactive molecules that are generated, for example, after interaction of integrins, extracellular matrix, and cytokines.…”

Aortic Aneurysms

“…55 Their recent work provided insights that mesenchymal stem cell infusion inhibited macrophage-produced high mobility group box 1 production and diminished release of proinflammatory cytokines, thereby preventing elastase-induced AAAs. 56 …”

Mesenchymal stem cell–derived conditioned medium attenuate angiotensin II‐induced aortic aneurysm growth by modulating macrophage polarization

“…Increasing evidence supports that MSCs provide the therapeutic potential to inhibit AA progression via paracrine effect. [9][10][11][12] BM-MSC-derived conditioned medium (MSCs-CM) is thought to be a potent secretory component of BM-MSCs containing specific cytokines, growth factors and small RNAs, which play an important role in MSC-mediated therapeutic effects. 13 Several recent studies have demonstrated that administration of MSCs-CM was as effective as BM-MSCs treatment itself in animal models of tissue injury and inflammatory diseases.…”