Extracellular Vesicles as Mediators of Cellular Crosstalk Between Immune System and Kidney Graft

Abstract

Extracellular vesicles (EVs) are known immune-modulators exerting a critical role in kidney transplantation (KT). EV bioactive cargo includes graft antigens, costimulatory/inhibitory molecules, cytokines, growth factors, and functional microRNAs (miRNAs) that may modulate expression of recipient cell genes. As paracrine factors, neutrophil-and macrophage-derived EVs exert immunosuppressive and immune-stimulating effects on dendritic cells, respectively. Dendritic cell-derived EVs mediate alloantigen spreading and modulate antigen presentation to T lymphocytes. At systemic level, EVs exert pleiotropic effects on complement and coagulation. Depending on their biogenesis, they can amplify complement activation or shed complement inhibitors and prevent cell lysis. Likewise, endothelial-and platelet-derived EVs can exert procoagulant/prothrombotic effects and also promote endothelial survival and angiogenesis after ischemic injury. Kidney endothelial-and tubular-derived EVs play a key role in ischemia-reperfusion injury (IRI) and during the healing process; additionally, they can trigger rejection by inducing both alloimmune and autoimmune responses. Endothelial EVs have procoagulant/pro-inflammatory effects and can release sequestered self-antigens, generating a tissue-specific autoimmunity. Renal tubule-derived EVs shuttle pro-fibrotic mediators (TGF-β and miR-21) to interstitial fibroblasts and modulate neutrophil and T-lymphocyte influx. These processes can lead to peritubular capillary rarefaction and interstitial fibrosis-tubular atrophy. Different EVs, including those from mesenchymal stromal cells (MSCs), have been employed as a therapeutic tool in experimental models of rejection and IRI. These particles protect tubular and endothelial cells (by inhibition of apoptosis and inflammation-fibrogenesis or by inducing autophagy) and stimulate tissue regeneration (by triggering angiogenesis, cell proliferation, and migration). Finally, urinary and serum EVs represent potential biomarkers for delayed graft function (DGF) and acute rejection. In conclusion, EVs sustain an intricate crosstalk between graft tissue and innate/adaptive immune systems. EVs play a major role in allorecognition, IRI, autoimmunity, and alloimmunity and are promising as biomarkers and therapeutic tools in KT.

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

“…EVs are then taken up by neighboring or distant target cells (paracrine or endocrine effect) [ 40 ] and mediate a wide range of physiological and pathological processes, including renal disease [ 41 ]. EVs also exert pleiotropic, immunomodulatory roles in KTx [ 42 ]. Their bioactive cargo includes graft antigens, costimulatory/inhibitory molecules, cytokines, growth factors and, as discussed before, functional miRNAs that modulate expression of recipient cell target genes.…”

Role of Extracellular Vesicles in Autoimmune Pathogenesis

“…Despite the fact that EVs can regulate the biological activity of many types of immune cells, including T cells and natural killer cells (NK cells), the most effective regulatory activity of EVs is granted by APCs ( 6 ). APCs primarily control immune function through membrane proteins—specifically, MHC class I and II molecules; costimulatory molecules, such as CD80, CD86; and adhesion molecules ( 29 – 31 ). Similarly, EVs derived from APCs are involved in this process ( 25 ).…”

Excretion of urine extracellular vesicles bearing markers of activated immune cells and calcium/phosphorus physiology differ between calcium kidney stone formers and non-stone formers

“…EVs secreted by these immune cells can serve as a biomarker of their presence and activation, and may also serve signaling functions in vivo, including antigen presentation, immune suppression, and tissue remodeling [30]. EVs secreted by innate immune cells such as macrophages appear to impact innate immune regulation primarily as pro-in ammatory and paracrine mediators [31]. In contrast, some subsets of immune cells and their signaling molecules can suppress an immune response [13,32].…”

“…In contrast, some subsets of immune cells and their signaling molecules can suppress an immune response [13,32]. For example, neutrophils secrete EVs that have anti-in ammatory and immunosuppressive effects, mainly on dendritic cells and macrophages [31].…”