Dendritic cells and macrophages in the kidney: a spectrum of good and evil

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.

Figure 1. The heterogeneous but overlapping phenotype and function of renal DC and Mac

DC are traditionally described as mediators of immune surveillance and antigen presentation and the primary determinants of antigenic fate through initiation of immune effector cell function or the development of tolerance. Mac also function as innate immune cells predominantly through phagocytosis, and production of toxic metabolites. However, the classical paradigm of DC versus Mac is increasingly indistinct within the kidney, as these cells exhibit overlapping surface markers, functional capabilities, and ontogenic pathways. Abbreviations: AT3 – antithrombin 3; Batf3 – basic leucine zipper transcription factor ATF-like 3; csf – colony stimulating factor; DC-SIGN – dendritic cell-specific ICAM-3-grabbing non-integrin; flt3 – fms-like tyrosine kinase 3; ICAM – intercellular adhesion molecule; Id2 – inhibitor of DNA binding 2; IRF – interferon regulatory factor; SIRPα – signal regulatory protein alpha; STAT – signal transducer and activator of transcription; Zbtbf46 – zinc finger and BTB domain containing 46 * denotes human markers only

Figure 2. Ontogeny of renal-resident DC and Mac

Bone marrow-resident monocyte-dendritic cell precursors (MDP) release monocytes to the peripheral circulation under homeostatic and inflammatory conditions. Cells also develop into common and pre-DC precursors (CDP and pre-DC) that migrate from blood to the renal interstitial compartment, with regular turnover. Pre-DC under the influence of different growth factors, become distinct, tissue-based subsets (broadly characterized as CX3CR1⁺ or CD103⁺) capable of exodus to the draining lymph node for antigen presentation to T cells. Pre-DC also give rise to plasmacytoid DC (pDC), although their presence in murine kidney is disputed.

Figure 3. Renal DC function in health and disease

DC provide homeostatic functions including tolerance to peripheral antigens typically cleared by the glomerulus, and anti-infectious immunosurveillance. Interaction with bacteria promotes generation of chemokines to attract effector cells, such as neutrophils. DC responsiveness and maturation state may be regulated by ongoing interaction with tubular epithelial cells. They also operate to exacerbate or mitigate a wide range of parenchymal disease and this role may be determined by either tissue-resident or influxing cells. Abbreviations: AKI – acute kidney injury; IRI – ischemia reperfusion injury; NTN – nephrotoxic nephritis; SLE – systemic lupus erythematosus; UUO – unilateral ureteral obstruction

Figure 4. Mac in renal disease

Tissue-resident Mac or infiltrating pro-inflammatory monocytes may become classically-activated (M1) to produce IL-12 and IL-23 and engage T cells for antigen presentation and activation or induce pro-fibrotic parenchymal change. M1 Mac may be reprogrammed to become alternatively-activated (M2) Mac by anti-inflammatory cytokines or apoptotic cell ingestion. M2 Mac may facilitate restoration of tubular cell integrity following injury . Mac may also express anti-inflammatory mediators such as HO-1 or IL-10 that act to limit tissue injury and promote resolution of inflammation, but may also drive pericyte and myofibroblast activation. Abbreviations: AKI – acute kidney injury; HO-1 – heme oxygenase-1; ICAM-1 – intercellular adhesion molecule-1; M-CSF – macrophage colony-stimulating factor (also known as csf-1); OPN – osteopontin; PDGF – platelet-derived growth factor; Wnt7b – wingless-related MMTV integration site 7B.