Targeting Interleukin-10 Restores Graft Microvascular Supply and Airway Epithelium in Rejecting Allografts

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.

Monitoring regulatory T cells as a prognostic marker in lung transplantation

“…TSG-6 can modulate matrix structure and organization by upregulating several regulatory cells, such as Tregs, M2 macrophages, Matrix metalloproteinases (MMPs), and associated anti-inflammatory cytokines, thereby suppressing proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and oxidative stress to prevent extensive tissue damage during inflammation ( 84 , 94 – 96 ). IL-10 enhances microvascular supply, tissue oxygenation, and airway epithelium regeneration in allografts through the surface expression of TSG-6, further supporting the therapeutic benefits during wound healing and tissue repair ( 46 , 65 , 66 , 81 ). The relationship between inflammation and fibrogenesis has led to IL-10 being identified as a potential antifibrotic target as well as a gatekeeper of fibrotic/antifibrotic signaling, so immune and cell-based therapies aiming to capitalize on IL-10 as a target could be effective in treating lung transplanted patients suffering from delayed would healing.…”

“…IL-10, an anti-inflammatory cytokine, favors tissue repair, and regulate FOXP3 ( 64 ). IL-10 is a potent antifibrotic, reparative, as well as vasculo-protective cytokine that assists in the repair of tissue following a sporadic alloimmune response during transplantation ( 46 , 65 – 71 ). The anti-inflammatory properties of IL-10 help to suppress the production of pro-inflammatory cytokines such as IFN- γ, IL-2, IL-3, and TNF- α by Th1 cells, mast cells, NK cells, endothelial cells, eosinophils, and macrophages ( 72 – 78 ).…”

“…In addition to limiting collateral tissue damage caused by uncontrolled immune responses, IL-10 helps maintain the regulatory microenvironment by upregulating TSG-6, M2 macrophages, and, tolerogenic dendritic cells (DC-10), antigen-specific T regulatory type 1 (Tr1), while suppressing Th1/Th17 effector immunity ( 65 , 67 , 68 , 71 , 73 , 79 , 80 ). Through the surface expression of TSG-6, FOXJ1, Fascin-1, and β-catenin proteins, IL-10 enhances microvascular supply, tissue oxygenation, and airway epithelium regeneration in allografts, further supporting the therapeutic benefits during wound healing and tissue repair ( 46 , 65 , 66 , 81 ).…”

“…In addition to limiting collateral tissue damage caused by uncontrolled immune responses, IL-10 helps maintain the regulatory microenvironment by upregulating TSG-6, M2 macrophages, and, tolerogenic dendritic cells (DC-10), antigen-specific T regulatory type 1 (Tr1), while suppressing Th1/Th17 effector immunity ( 65 , 67 , 68 , 71 , 73 , 79 , 80 ). Through the surface expression of TSG-6, FOXJ1, Fascin-1, and β-catenin proteins, IL-10 enhances microvascular supply, tissue oxygenation, and airway epithelium regeneration in allografts, further supporting the therapeutic benefits during wound healing and tissue repair ( 46 , 65 , 66 , 81 ). The relationship between inflammation and fibrogenesis has led to IL-10 being identified as a potential antifibrotic target as well as a gatekeeper of fibrotic/antifibrotic signaling, so immune and cell-based therapies aiming to capitalize on IL-10 as a target could be effective in treating lung transplanted patients suffering from delayed would healing.…”

Acellular Biomaterials Associated with Autologous Bone Marrow-Derived Mononuclear Stem Cells Improve Wound Healing through Paracrine Effects

“…Some studies have revealed that AM and BMSCs can express angiogenic factors, which is crucial to tissue flap regeneration and a complex process; it involves the proliferation of endothelial cells and the cooperation of various growth factors [ 24 , 25 , 26 ]. In the current study, immunohistochemical staining together with the cytokine level showed that the IL-1 and IL-10 were overexpressed at the late stages of healing (28 days postoperative); these data corroborate with the literature.…”