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Key Points The mTOR pathway has a central role in the regulation of cell metabolism, growth and proliferation Pharmacological inhibition of mTOR and selective gene targeting of mTORC1 or mTORC2 in podocytes and tubular epithelial cells has helped to elucidate their role in renal cell homeostasis, including in autophagy Mechanistic insights into the roles of mTOR complexes in regulating immune cell function are helping to improve understanding of the effects of mTOR inhibitors in renal disease and transplant rejection mTOR is increasingly recognized as having a fundamental role in the development of glomerular disease and in acute kidney injury; its role in fibrotic kidney disease is less certain New generation dual mTORC1 and mTORC2 inhibitors offer potential for the treatment of renal cell carcinoma mTOR inhibitors are associated with reduced rates of skin cancer and cytomegalovirus infection in renal transplant recipients The mTOR pathway has a role in the development of renal disease, kidney transplant rejection and malignancies. Here, the authors discuss the mechanisms by which mTOR complexes drive the pathogenesis of these diseases as well as the therapeutic potential of mTOR inhibitors. The mTOR pathway has a central role in the regulation of cell metabolism, growth and proliferation. Studies involving selective gene targeting of mTOR complexes (mTORC1 and mTORC2) in renal cell populations and/or pharmacologic mTOR inhibition have revealed important roles of mTOR in podocyte homeostasis and tubular transport. Important advances have also been made in understanding the role of mTOR in renal injury, polycystic kidney disease and glomerular diseases, including diabetic nephropathy. Novel insights into the roles of mTORC1 and mTORC2 in the regulation of immune cell homeostasis and function are helping to improve understanding of the complex effects of mTOR targeting on immune responses, including those that impact both de novo renal disease and renal allograft outcomes. Extensive experience in clinical renal transplantation has resulted in successful conversion of patients from calcineurin inhibitors to mTOR inhibitors at various times post-transplantation, with excellent long-term graft function. Widespread use of this practice has, however, been limited owing to mTOR-inhibitor- related toxicities. Unique attributes of mTOR inhibitors include reduced rates of squamous cell carcinoma and cytomegalovirus infection compared to other regimens. As understanding of the mechanisms by which mTORC1 and mTORC2 drive the pathogenesis of renal disease progresses, clinical studies of mTOR pathway targeting will enable testing of evolving hypotheses.

Key Points The atypical serine/threonine protein kinase mammalian target of rapamycin (mTOR) has an important role in the modulation of both innate and adaptive immune responses. A complex formed between the immunosuppressive drug rapamycin and the immunophilin FK506-binding protein 1A, 12 kDA (FKBP12) inhibits mTOR kinase activity. mTOR functions in at least two multi-protein complexes: mTOR complex 1 (mTORC1) and mTORC2. mTOR in mTORC1 is highly sensitive to inhibition by rapamycin, whereas mTOR in mTORC2 is resistant to rapamycin. mTORC1 regulates cell growth downstream of phosphoinositide 3-kinase–AKT signalling, in which active mTORC1 phosphorylates S6 kinase (S6K1) and the eukaryotic translation initiation factor-binding protein 1 (EIF4EBP1). Both of these activities promote mRNA translation and cell growth. Rapamycin exerts many effects on the differentiation and function of professional antigen-presenting cells (APCs). mTOR inhibition by rapamycin impedes antigen uptake and can modulate antigen presentation by dendritic cells (DCs); its differential effects on cytokine production and chemokine receptor expression by DCs regulate interactions between innate and adaptive immune cells. Recent findings have shed light on previously unappreciated effects of mTOR inhibition on T cells. Rapamycin induces thymic involution, whereas the ontogeny of naturally occurring regulatory T (T Reg ) cells seems to be less affected. During conventional T cell activation, rapamycin-mediated mTOR inhibition blocks cell cycle progression and can sequester activated T cells in secondary lymphoid tissues. By contrast, rapamycin causes an increase in the frequency of FOXP3 (forkhead box P3) + T cells, reflecting both the ability of T Reg cells to proliferate in the presence of rapamycin and the promotion of FOXP3 expression in peripheral T cells that are then converted into modulators of immune reactivity. mTOR inhibition is a promising therapeutic strategy to prevent rejection in transplantation and for autoimmune disease. Differential effects of rapamycin on T cells and T Reg cells (both naturally occurring and inducible) favour its ability to promote tolerance in tolerance-enhancing protocols. In addition, adoptively transferred rapamycin-conditioned APCs inhibit organ allograft rejection and graft-versus-host disease following haematopoietic cell transplantation. Ongoing and future areas of enquiry, which could prove fruitful, include distinguishing the role of mTORC1 and mTORC2 in the regulation of immune responses and tolerance, investigating the role of the mTOR–survivin–aurora B complex in T cell activation and ascertaining the mechanisms that determine T Reg cell resistance to rapamycin and mTOR-mediated regulation of FOXP3 expression, as well as their relevance to therapy. Angus Thomson and colleagues describe the consequences of mammalian target of rapamycin (mTOR) inhibition by rapamycin on dendritic cells, effector T cells and regulatory T cells. These effects make mTOR inhibition a promising immunosuppressive, but tolerance-promoting, therapeutic strategy. The potent immunosuppressive action of rapamycin is commonly ascribed to inhibition of growth factor-induced T cell proliferation. However, it is now evident that the serine/threonine protein kinase mammalian target of rapamycin (mTOR) has an important role in the modulation of both innate and adaptive immune responses. mTOR regulates diverse functions of professional antigen-presenting cells, such as dendritic cells (DCs), and has important roles in the activation of effector T cells and the function and proliferation of regulatory T cells. In this Review, we discuss our current understanding of the mTOR pathway and the consequences of mTOR inhibition, both in DCs and T cells, including new data on the regulation of forkhead box P3 expression.

Dendritic cells (DCs) are highly specialized, bone marrow (BM)-derived antigen-processing and -presenting cells crucial to the induction, integration and regulation of innate, and adaptive immunity. They are stimulated by damage-associated molecular patterns (DAMPS) via pattern recognition receptors to promote inflammation and initiate immune responses. In addition to residing within the parenchyma of all organs as part of the heterogeneous mononuclear phagocyte system, DCs are an abundant component of the inflammatory cell infiltrate that appears in response to ischemia reperfusion injury (IRI). They can play disparate roles in the pathogenesis of IRI since their selective depletion has been found to be protective, deleterious, or of no benefit in mouse models of IRI. In addition, administration of DC generated and manipulated can protect organs from IRI by suppressing inflammatory cytokine production, limiting the capacity of DCs to activate NKT cells, or enhancing regulatory T cell function. Few studies however have investigated specific signal transduction mechanisms underlying DC function and how these affect IRI. Here, we address current knowledge of the role of DCs in regulation of IRI, current gaps in understanding and prospects for innovative therapeutic intervention at the biological and pharmacological levels.

Immunomodulation holds therapeutic promise against brain injuries, but leveraging this approach requires a precise understanding of mechanisms. We report that [CD8.sup.+][CD122.sup.+][CD49d.sup.lo] T regulatory-like cells ([CD8.sup.+] TRLs) are among the earliest lymphocytes to infiltrate mouse brains after ischemic stroke and temper inflammation; they also confer neuroprotection. TRL depletion worsened stroke outcomes, an effect reversed by [CD8.sup.+] TRL reconstitution. The CXCR3/CXCL10 axis served as the brain-homing mechanism for [CD8.sup.+] TRLs. Upon brain entry, [CD8.sup.+] TRLs were reprogrammed to upregulate leukemia inhibitory factor (LIF) receptor, epidermal growth factor-like transforming growth factor (ETGF), and interleukin 10 (IL-10). LIF/LIF receptor interactions induced ETGF and IL-10 production in [CD8.sup.+] TRLs. While IL-10 induction was important for the Anti-inflammatory effects of [CD8.sup.+] TRLs, ETGF provided direct neuroprotection. Poststroke intravenous transfer of [CD8.sup.+] TRLs reduced infarction, promoting long-term neurological recovery in young males or aged mice of both sexes. Thus, these unique [CD8.sup.+] TRLs serve as early responders to rally defenses against stroke, offering fresh perspectives for clinical translation.

A comparison of pre-clinical transplant models and of solid organs transplanted in routine clinical practice demonstrates that the liver is most amenable to the development of immunological tolerance. This phenomenon arises in the absence of stringent conditioning regimens that accompany published tolerizing protocols for other organs, particularly the kidney. The unique immunologic properties of the liver have assisted our understanding of the alloimmune response and how it can be manipulated to improve graft function and survival. This review will address important findings following liver transplantation in both animals and humans, and how these have driven the understanding and development of therapeutic immunosuppressive options. We will discuss the liver's unique system of immune and non-immune cells that regulate immunity, yet maintain effective responses to pathogens, as well as mechanisms of liver transplant tolerance in pre-clinical models and humans, including current immunosuppressive drug withdrawal trials and biomarkers of tolerance. In addition, we will address innovative therapeutic strategies, including mesenchymal stem cell, regulatory T cell, and regulatory dendritic cell therapy to promote liver allograft tolerance or minimization of immunosuppression in the clinic.

Key Points Dendritic cells (DCs) and macrophages are distinct cell types, but demonstrate similarities in terms of ontogeny, phenotype, and function Both of these cell types are present within the renal interstitium and are critical to homeostatic regulation of the kidney environment The numbers of DCs and macrophages in the kidney increase following renal injury A variety of DC and macrophage subtypes exist, each with distinct phenotypes and activities, and many can be identified based on panels of cellular markers The manifestation of glomerular or tubular kidney disease, as well as disease outcome in preclinical models, is determined by the subtype of DC and/or macrophage involved A number of pharmacological or genetic approaches are available to deplete or eliminate DCs or macrophages in preclinical models, but the effects of such interventions are not renal-specific Renal dendritic cells and macrophages are key factors in the initiation and propagation of renal disease and tissue regeneration. In this Review, the authors discuss the common and distinct characteristics of dendritic cells and macrophages as well as current understanding of the renal-specific functions of these important phagocytic, antigen-presenting cell types in potentiating or mitigating intrinsic kidney disease. Renal dendritic cells (DCs) and macrophages represent a constitutive, extensive and contiguous network of innate immune cells that provide sentinel and immune-intelligence activity; they induce and regulate inflammatory responses to freely filtered antigenic material and protect the kidney from infection. Tissue-resident or infiltrating DCs and macrophages are key factors in the initiation and propagation of renal disease, as well as essential contributors to subsequent tissue regeneration, regardless of the aetiological and pathogenetic mechanisms. The identification, and functional and phenotypic distinction of these cell types is complex and incompletely understood, and the same is true of their interplay and relationships with effector and regulatory cells of the adaptive immune system. In this Review, we discuss the common and distinct characteristics of DCs and macrophages, as well as key advances that have identified the renal-specific functions of these important phagocytic, antigen-presenting cells, and their roles in potentiating or mitigating intrinsic kidney disease. We also identify remaining issues that are of priority for further investigation, and highlight the prospects for translational and therapeutic application of the knowledge acquired.

The triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor that affects cellular phenotypes by modulating phagocytosis and metabolism, promoting cell survival, and counteracting inflammation. Its role in renal injury, in particular, unilateral ureteral obstruction (UUO) or ischemia-reperfusion injury (IRI)-induced renal injury remains unclear. In our study, WT and Trem2 −/− mice were employed to evaluate the role of TREM2 in renal macrophage infiltration and tissue injury after UUO. Bone marrow-derived macrophages (BMDM) from both mouse genotypes were cultured and polarized for in vitro experiments. Next, the effects of TREM2 on renal injury and macrophage polarization in IRI mice were also explored. We found that TREM2 expression was upregulated in the obstructed kidneys. TREM2 deficiency exacerbated renal inflammation and fibrosis 3 and 7 days after UUO, in association with reduced macrophage infiltration. Trem2 −/− BMDM exhibited increased apoptosis and poorer survival compared with WT BMDM. Meanwhile, TREM2 deficiency augmented M1 and M2 polarization after UUO. Consistent with the in vivo observations, TREM2 deficiency led to increased polarization of BMDM towards the M1 proinflammatory phenotype. Mechanistically, TREM2 deficiency promoted M1 and M2 polarization via the JAK-STAT pathway in the presence of TGF-β1, thereby affecting cell survival by regulating mTOR signaling. Furthermore, cyclocreatine supplementation alleviated cell death caused by TREM2 deficiency. Additionally, we found that TREM2 deficiency promoted renal injury, fibrosis, and macrophage polarization in IRI mice. The current data suggest that TREM2 deficiency aggravates renal injury by promoting macrophage apoptosis and polarization via the JAK-STAT pathway. These findings have implications for the role of TREM2 in the regulation of renal injury that justify further evaluation.

Abstract Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily. As an amplifier of the inflammatory response, TREM-1 is mainly involved in the production of inflammatory mediators and the regulation of cell survival. TREM-1 has been studied in infectious diseases and more recently in non-infectious disorders. More and more studies have shown that TREM-1 plays an important pathogenic role in kidney diseases. There is evidence that TREM-1 can not only be used as a biomarker for diagnosis of disease but also as a potential therapeutic target to guide the development of novel therapeutic agents for kidney disease. This review summarized molecular biology of TREM-1 and its signaling pathways as well as immune response in the progress of acute kidney injury, renal fibrosis, diabetic nephropathy, immune nephropathy, and renal cell carcinoma.

Obesity-associated increases in adipose tissue (AT) CD11c+ cells suggest that dendritic cells (DC), which are involved in the tissue recruitment and activation of macrophages, may play a role in determining AT and liver immunophenotype in obesity. This study addressed this hypothesis. With the use of flow cytometry, electron microscopy, and loss-and-gain of function approaches, the contribution of DC to the pattern of immune cell alterations and recruitment in obesity was assessed. In AT and liver there was a substantial, high-fat diet (HFD)–induced increase in DC. In AT, these increases were associated with crown-like structures, whereas in liver the increase in DC constituted an early and reversible response to diet. Notably, mice lacking DC had reduced AT and liver macrophages, whereas DC replacement in DC-null mice increased liver and AT macrophage populations. Furthermore, delivery of bone marrow–derived DC to lean wild-type mice increased AT and liver macrophage infiltration. Finally, mice lacking DC were resistant to the weight gain and metabolic abnormalities of an HFD. Together, these data demonstrate that DC are elevated in obesity, promote macrophage infiltration of AT and liver, contribute to the determination of tissue immunophenotype, and play a role in systemic metabolic responses to an HFD.

The healthy immune system has natural checkpoints that temper pernicious inflammation. Cells mediating these checkpoints include regulatory T cells, regulatory B cells, regulatory dendritic cells, microglia, macrophages and monocytes. Here, we highlight discoveries on the beneficial functions of regulatory immune cells and their mechanisms of action and evaluate their potential use as novel cell-based therapies for brain disorders. Regulatory immune cell therapies have the potential not only to mitigate the exacerbation of brain injury by inflammation but also to promote an active post-injury brain repair programme. By harnessing the reparative properties of these cells, we can reduce over-reliance on medications that mask clinical symptoms but fail to impede or reverse the progression of brain disorders. Although these discoveries encourage further testing and genetic engineering of regulatory immune cells for the clinical management of neurological disorders, a number of challenges must be surmounted to improve their safety and efficacy in humans.