The divergent roles of macrophages in solid organ transplantation

Abstract

Purpose of review This review summarizes the phenotype and function of macrophages in the context of solid organ transplantation and will focus on fundamental insights into their paradoxical pro-inflammatory versus suppressive function. We will also discuss the therapeutic potential of regulatory macrophages in tolerance induction. Recent findings Macrophages are emerging as an essential element of solid organ transplantation. Macrophages are involved in the pathogenesis of ischemia reperfusion injury, as well as both acute and chronic rejection, exacerbating injury through secretion of inflammatory effectors and by amplifying adaptive immune responses. Notably, not all responses associated with macrophages are deleterious to the graft, and graft protection can in fact be conferred by macrophages. This has been attributed to the presence of macrophages with tissue-repair capabilities, as well as the effects of regulatory macrophages. Summary The explosion of new information on the role of macrophages in solid organ transplantation has opened up new avenues of research and the possibility of therapeutic intervention. However, the role of myeloid cells in graft rejection, resolution of rejection and tissue repair remains poorly understood. A better understanding of plasticity and regulation of monocyte polarization is vital for the development of new therapies for the treatment of acute and chronic transplant rejection.

Inflammatory macrophage–associated 3-gene signature predicts subclinical allograft injury and graft survival

“…We also demonstrated that the CRM is mechanistically involved in graft injury by identifying two FDA-approved drugs that reduced graft-infiltrating immune cells and extended graft survival in a mouse model of cardiac transplantation and electronic health records of renal transplant patients (7). Collectively, these results suggest the possibility of a gene signature common to both ACR and AMR (10)(11)(12).…”

“…Macrophage infiltration has been implicated in both AR (13) and chronic graft failure (10,11), yet a precise role for this cell type in organ transplantation remains unclear (12). Macrophages take on diverse phenotypic states in response to environmental stimuli, with activation characterized by a spectrum of transcriptional reprogramming (14), ranging from an antiinflammatory phenotype in the presence of IL-4 or IL-10 to a proinflammatory phenotype in the presence of IFN-γ, referred to as M(IL-4), M(IL-10), and M(IFN-γ), respectively (15).…”

Macrophage/monocyte-specific deletion of Ras homolog gene family member A (RhoA) downregulates fractalkine receptor and inhibits chronic rejection of mouse cardiac allografts

“…Although phenomenon of chronic rejection, by virtue of its complexity and multifactoriality is still not well understood, it is known that monocytes and macrophages play an important role in this process (1–2). Mammalian organs (including heart) contain various subsets of macrophages with different origin (embryonic yolk sack versus blood or bone marrow-derived) and functions (3–6).…”

Minimizing the risk of allo-sensitization to optimize the benefit of allogeneic cardiac-derived stem/progenitor cells

“…Other innate immune cells including macrophages express different sub-classes of Fcγ receptors and might mediate ADCC and graft rejection4041. For instance, in allogeneic hepatocytes and islet cell transplantation models, the presence of alloantibodies resulted in macrophage-mediated ADCC and graft rejection4243.…”