The Evolving Roles of Macrophages in Organ Transplantation

Abstract

Organ transplantation is a life-saving strategy for patients with end-stage organ failure. Over the past few decades, organ transplantation has achieved an excellent success in short-term survival but only a marginal improvement in long-term graft outcomes. The pathophysiology of graft loss is multifactorial and remains incompletely defined. However, emerging evidence suggests macrophages as crucial mediators of acute and chronic allograft immunopathology. In this process, macrophage-mediated mobilization of first-line defenses, particularly phagocytosis and the release of acute inflammatory mediators, is important, but macrophages also launch adaptive alloimmune reactions against grafts through antigen processing and presentation, as well as providing costimulation. Additionally, crosstalk with other immune cells and graft endothelial cells causes tissue damage or fibrosis in transplanted organs, contributing to graft loss or tolerance resistance. However, some macrophages function as regulatory cells that are capable of suppressing allogeneic T cells, inhibiting DC maturation, inducing the differentiation of Tregs, and subsequently promoting transplant tolerance. This functional diversity of macrophages in organ transplantation is consistent with their heterogeneity. Although our knowledge of the detrimental or beneficial effects of macrophages on transplants has exponentially increased, the exact mechanisms controlling macrophage functions are not yet completely understood. Here, we review recent advances in our understanding of the multifaceted nature of macrophages, focusing on their evolving roles in organ transplantation and the mechanisms involved in their activation and function in allograft transplantation. We also discuss potential therapeutic options and opportunities to target macrophage to improve the outcomes of transplant recipients.

The Immunological Basis of Liver Allograft Rejection

“…The macrophage response is often conceptualized as being either pro-inflammatory, stimulated by IFN-γ and lipopolysaccharide (the so-called M1 phenotype) or immunosuppressive, stimulated by IL-4 and IL-13 (the M2 phenotype). In acute rejection many macrophages show features of polarization toward an M1 phenotype producing pro-inflammatory cytokines such as IL-1, IL-12, IL-18, IL-6, IL-23, TNF-α and IFN-γ and reactive oxygen and nitrogen species which cause direct cell damage and co-ordinate a pro-inflammatory immune response ( 62 ). Recognition of damaged allograft tissue is through the pattern recognition receptors such as the toll-like receptors and macrophages have a major phagocytic role in the clearing of damaged cells ( 63 ).…”

Role of the Monocyte–Macrophage System in Normal Pregnancy and Preeclampsia

“…Injection of the autologous monocyte-derived M2-polarized macrophages at a certain time of gestation (or at the stage of its planning by taking into account the risks of PE) may evolve into a new strategy for PE treatment. Such therapy seems to be promising due to reports about the absence of adverse reactions and long-term side effects after macrophages transplantation in other diseases [120,121]. A possible side effect of the proposed therapy may be the phenomenon of maternal–fetal cellular trafficking—the ability of mother and fetus cells pass the placental barrier [122].…”

Macrophages in Organ Transplantation

“…Tissueresident macrophages (TRMs) arise from fetal liver or yolk-sac progenitors and are phenotypically distinct from monocytederived macrophages in steady state conditions (84). While TRMs are primarily characterized by the expression of CD11b, F4/80, CD64, CD68 and MerTK and low levels of MHC-II on the cell surface in mice, monocyte-derived macrophages are characterized by CD11b, CD209, CD64 and MerTK expression on the cell surface (85). TRMs are functionally considered to be immunosuppressive because of their fundamental roles in maintaining homeostasis, inhibiting T cell activation and promoting the resolution of inflammation (75,86).…”