Abstract
Interleukin-10 (IL-10) is a vital regulatory cytokine, which plays a constructive role in maintaining immune tolerance during an alloimmune inflammation. Our previous study highlighted that IL-10 mediated immunosuppression established the immune tolerance phase and thereby modulated both microvascular and epithelial integrity, which affected inflammation-associated graft malfunctioning and sub-epithelial fibrosis in rejecting allografts. Here, we further investigated the reparative effects of IL-10 on microvasculature and epithelium in a mouse model of airway transplantation. To investigate the IL-10 mediated microvascular and epithelial repair, we depleted and reconstituted IL-10, and monitored graft microvasculature, airway epithelium, and associated repair proteins. Our data demonstrated that both untreated control allografts and IL-10 (−) allografts showed a significant early (d6) increase in microvascular leakiness, drop-in tissue oxygenation, blood perfusion, and denuded airway epithelium, which is associated with loss of adhesion protein Fascin-1 and β-catenin on vascular endothelial cells at d10 post-transplantation. However, IL-10 (+) promotes early microvascular and airway epithelial repair, and a proportional increase in endothelial Fascin-1, and β-catenin at d10 post-transplantation. Moreover, airway epithelial cells also express a significantly higher expression of FOXJ1 and β-catenin in syngrafts and IL-10 (+) allografts as compared to IL-10 (−) and untreated controls at d10 post-transplantation. Collectively, these findings demonstrated that IL-10 mediated microvascular and epithelial changes are associated with the expression of FOXJ1, β-catenin, and Fascin-1 proteins on the airway epithelial and vascular endothelial cells, respectively. These findings establish a potential reparative modulation of IL-10 associated microvascular and epithelial repair, which could provide a vital therapeutic strategy to facilitate graft repair in clinical settings.
Highlights
Interleukin-10 is an anti-inflammatory cytokine secreted mainly by regulatory cells and plays a vital role in cell and tissue repair [1,2]
FOXJ1 has been associated with ciliogenesis in airway epithelium and affected largely due to the severe hypoxic and ischemic state of the tissue [34]. β-Catenin plays a vital role in cell survival and proliferation; little is known regarding its role in endothelial cells
Our microvascular leakiness data demonstrated that both untreated control allografts and IL-10 (−) allografts showed a significant microvascular leakiness (p < 0.05) and showed a significantly hypoxic and ischemic phase (p < 0.05) as compared to corresponding syngrafts and IL-10 (+) allografts at d6 post-transplantation
Summary
Interleukin-10 is an anti-inflammatory cytokine secreted mainly by regulatory cells and plays a vital role in cell and tissue repair [1,2]. Preclinical and clinical lung transplantation studies demonstrated that Tregs and their associated mediators modulate both airway epithelium and vascular endothelium of grafted tissue, which effectively modulates the expression of various adhesion proteins on the surface of both airway epithelium and microvessels within the graft [22,23,24,25,26,27,28,29,30,31]. Inflammation-associated immune modulation affects the extracellular expression of both β-catenin and Fascin-1 on epithelial and endothelial cells, respectively, which is crucial to tissue remodeling during allograft rejection. We demonstrated that therapeutic doses of IL-10 are sufficient to affect tissue microvasculature, associated inflammatory, and regulatory gene expression in a mouse model of airway transplantation, which establishes a vital therapeutic scope of IL-10 to rescue rejecting transplants for future translational studies. We aimed to investigate the effects of IL-10 on graft microvascular and epithelial repair during allograft rejection
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