IL-10 Mediated Immunotolerance Augments TSG-6 Expression and Prevents Subepithelial Fibrosis in Mouse Airway Allografts

Abstract

Background: Regulatory T cells (CD4+FOXP3+ Tregs) play a crucial role in the maintenance of immunotolerance to alloantigens, which is accompanied by the removal of alloreactive T effector cells (Teffs), or by polarizing Teffs-Tregs ratio in favor of Tregs to suppress alloimmune inflammation and rescue allograft from microvascular associated injuries and progression of fibrosis during transplantation. Inflammation-induced and microvascular associated airway epithelial injuries are the key pathological source of graft malfunctioning and subepithelial fibrosis, which play a major role in the progression of chronic rejection. The present study was designed to investigate the therapeutic impact of Interleukin-10 (IL-10) on immunotolerance, in particular, the reparative microenvironment, which negate airway epithelial injury, and fibrosis during graft rejection. Methods: Here, we depleted and reconstituted IL-10, and serially monitored the phase of immunotolerance, graft microvasculature, proinflammatory cytokines, airway epithelium, and subepithelial collagen in rejecting airway transplants. Results: We demonstrated that the IL-10 depletion suppresses Tregs, Tumor necrosis factor-inducible gene 6 (TSG-6) protein, graft microvasculature, and establishes a pro-inflammatory phase, which favors airway epithelial injury and subepithelial collagen deposition while the IL-10 reconstitution induces Tregs, TSG-6 expression, graft microvasculature, and establishes an immunotolerance phase, which favors airway epithelial repair and subepithelial collagen suppression. Interpretation: Collectively, these findings establish a potential reparative modulation of IL-10 associated immunotolerance on microvascular, epithelial, and fibrotic remodeling, which could provide a vital therapeutic option to rescue rejecting transplants in clinical settings. Funding Statement: This research study was financed under the RAC 2140 036 to MAK (PI) by the Office of Research Administration at the KFSH&RC, Riyadh, Saudi Arabia. Declaration of Interests: All authors declare that they have no other competing interests as defined by Journal, or other interests that might be perceived to influence the results and discussion reported in this paper. Ethics Approval Statement: All material is original and has not been reproduced from another source, and experiments using animals were approved by ACUC at the KFSH&RC.