Hypoxia-induced complement dysregulation is associated with microvascular impairments in mouse tracheal transplants

Abstract

Abstract Background Complement Regulatory Proteins (CRPs), especially CD55 primarily negate complement factor 3-mediated injuries and maintain tissue homeostasis during complement cascade activation. Complement activation and regulation during alloimmune inflammation contribute to allograft injury and therefore we proposed to investigate a crucial pathological link between vascular expression of CD55, active-C3, T cell immunity and associated microvascular tissue injuries during allograft rejection. Methods Balb/c→C57BL/6 allografts were examined for microvascular deposition of CD55, C3d, T cells, and associated tissue microvascular impairments during rejection in mouse orthotopic tracheal transplantation. Results Our findings demonstrated that hypoxia-induced early activation of HIF-1α favors a cell-mediated inflammation (CD4+, CD8+, and associated proinflammatory cytokines, IL-2 and TNF-α), which proportionally triggers the downregulation of CRP-CD55, and thereby augments the uncontrolled release of active-C3, and Caspase-3 deposition on CD31+ graft vascular endothelial cells. These molecular changes are pathologically associated with microvascular deterioration (low tissue O2 and Blood flow) and subsequent airway epithelial injuries of rejecting allografts as compared to non-rejecting syngrafts. Conclusion Together, these findings establish a pathological correlation between complement dysregulation, T cell immunity, and microvascular associated injuries during alloimmune inflammation in transplantation.