Nature Reviews Nephrology | Review
Renal dendritic cells and macrophages are key factors in the initiation and propagation of renal disease and tissue regeneration. This Review discusses 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.
Abstract | 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.
Rogers, N. M. et al. Nat. Rev. Nephrol. advance online publication 30 September 2014; doi:10.1038/nrneph.2014.170
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Figure 1: The heterogeneous but overlapping phenotype and functions of renal DCs and macrophages.
DCs are traditionally described as mediators of immune surveillance and antigen presentation, and as the primary determinants of responses to antigens—through initiation of either immune effector-cell functions or the development of tolerance. Macrophages also function as innate immune cells, predominantly through phagocytosis and production of toxic metabolites. However, the classical paradigm of DC versus macrophage phenotypes and functions is increasingly indistinct within the kidney, as these cells exhibit overlapping surface markers, functional capabilities, and ontogenic pathways. This molecular and phenotypic overlap between cell types and subsets complicates their identification and evaluation. *Marker described only in humans. Abbreviations: B-ATF-3, basic leucine zipper transcription factor ATF-like 3; BDCA-1, blood dendritic cell antigen 1; CCR, CC chemokine receptor; CSF-1R, colony-stimulating factor 1 receptor; CX3CR1, CX3C chemokine receptor 1; DC, dendritic cell; DC-SIGN, dendritic-cell-specific ICAM-3-grabbing non-integrin; ECM, extracellular matrix; EMR1, EGF-like module-containing mucin-like hormone receptor-like 1; FcγR(II/III), low affinity IgG Fc region receptor (II/III); FLT3, fms-like tyrosine kinase 3; Gr-1, granulocyte-differentiation antigen-1; ICAM-1, intercellular adhesion molecule 1; ID-2, inhibitor of DNA binding 2; IL-4R, IL-4 receptor; IL-10R, IL-10 receptor; IRF, interferon regulatory factor; Ly6(C/G), lymphocyte antigen 6(C/G); SIRPα, signal-regulatory protein α (also known as tyrosine-protein phosphatase nonreceptor type substrate 1); STAT3, signal transducer and activator of transcription 3; ZBTB46, zinc finger and BTB domain containing protein 46.
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Figure 2: The ontogeny of kidney-resident DCs and macrophages.
Bone-marrow-resident MDPs differentiate into monocytes that are released to the peripheral circulation under homeostatic and inflammatory conditions. MDPs also develop into CDPs, which subsequently differentiate to pre-DCs that can migrate from bone marrow to the renal interstitial compartment via the blood, with regular turnover. Under the influence of different chemokines and growth factors, the pre-DCs differentiate to form distinct, tissue-based DC subsets (broadly characterized as CX3CR1+ DCs or CD103+ DCs) that are capable of exodus to the draining lymph nodes where they can present antigens to B cells and T cells. Monocytes can also localize to the kidney under the influence of chemokines such as CCR2, and subsequently differentiate into DCs. Pre-DCs also give rise to pDC, although the presence of pDCs in kidneys of mice is disputed (dashed arrow). Abbreviations: B-ATF-3, basic leucine zipper transcription factor ATF-like 3; BDCA-(1/2), blood dendritic cell antigen (1/2); CCL(19/21), CC chemokine ligand (19/21); CCR(2/7), CC chemokine receptor (2/7); CDP, common dendritic cell precursor; CLEC4K, C-type lectin domain family 4 member K; CLEC9A, C-type lectin domain family 9 member A; CSF-1, colony-stimulating factor 1; CSF-1R, CSF-1 receptor; CX3CR1, CX3C chemokine receptor 1; DC, dendritic cell; DC-SIGN, dendritic-cell-specific ICAM-3-grabbing non-integrin; FLT3, fms-like tyrosine kinase 3; FLT3LG, FLT3 ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; Ly6(C/G), lymphocyte antigen 6(C/G); M-CSF, macrophage colony-stimulating factor; MDP, monocyte–DC precursor; pDC, plasmacytoid DC.
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Figure 3: Renal DC function in health and disease.
DCs perform homeostatic functions, including induction of tolerance to peripheral antigens typically cleared by the glomerulus, such as albumin, and anti-infection immunosurveillance. Interaction of DCs with bacteria causes them to generate chemokines to attract effector cells, such as neutrophils. The kidney-resident DCs also operate to exacerbate (proinflammatory DCs) or mitigate (anti-inflammatory DCs) a wide range of parenchymal disease, and the role of these cells in disease might be determined by either tissue-resident cells or influxing cells and antigens. For example, the responsiveness and maturation state of DCs might be regulated by ongoing interactions with tubular epithelial cells. Abbreviations: AKI, acute kidney injury; DC, dendritic cell; IRI, ischaemia–reperfusion injury; LPS, lipopolysaccharide; NTN, nephrotoxic nephritis; SLE, systemic lupus erythematosus; TH17, type 17 T-helper; UUO, unilateral ureteral obstruction.
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Figure 4: Macrophages in renal disease.
Tissue-resident macrophages or infiltrating proinflammatory monocytes can become classically activated by exposure to danger-associated molecular patterns or proinflammatory cytokines to take on an M1 phenotype, associated with production of IL-12 and IL-23, engagement of T cells for antigen presentation, activation or exacerbation of profibrotic parenchymal changes, and direct and indirect tissue injury. M1 macrophages can be reprogrammed to become alternatively activated M2 macrophages by stimulation with anti-inflammatory cytokines, such as IL-10 or CSF-1, or ingestion of apoptotic cells. M2 macrophages might facilitate and coordinate restoration of tubular cell and, therefore, kidney tubule integrity following injury. M2 macrophages can also express anti-inflammatory mediators, such as HO-1 and IL-10, which act to limit tissue injury and promote resolution of inflammation, but might also drive pericyte and myofibroblast activation through production of TGF-β, galectin 3 and PDGF. Abbreviations: AKI, acute kidney injury; CSF-1, colony-stimulating factor 1; ECM, extracellular matrix; HO-1, haem oxygenase-1; ICAM-1, intercellular adhesion molecule 1; M-CSF, macrophage colony-stimulating factor; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor β; Wnt7b, wingless-related MMTV integration site 7B.
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