Renal Dendritic Cells: The Long and Winding Road
Authors: A. Richard Kitching, Joshua D. Ooi
Journal: Journal of the American Society of Nephrology (2017)

In the tubulointerstitial compartment and perivascular areas, there are networks of mononuclear phagocytes that include macrophages and dendritic cells (DCs).1–3 There is substantial overlap between these cell types, with both cell types being able to act innately to secrete cytokines and other soluble factors.4 However, although macrophages can present antigen, DCs are the real antigen-presenting "professionals." DCs are highly efficient in presenting antigen in the form of peptides to T lymphocytes to both activate naïve cells and allow antigen-specific recognition in inflamed tissue. Because the kidney is a complex organ influenced by multiple metabolic and immune stimuli, DCs are relevant to not only classic antigen presentation and recognition but also, innate inflammation. A study published in this issue of the Journal of the American Society of Nephrology (JASN) furthers our understanding of the nature of the renal mononuclear cells.5 It focuses on the identification of renal DCs using fate-mapping markers and the role of renal DCs independent of their role in antigen presentation (Figure 1).Figure 1.: Differences between renal DCs and renal macrophages on the basis of published data and the paper of Brähler et al. 5Cells of the monocyte/macrophage lineage within the kidney play multiple roles in innate inflammation and linking innate and adaptive immunity. For example, monocytes patrol renal vessels,6,7 and macrophages reside in the kidney, where they sense danger and trigger injury. DCs, like macrophages, sense danger and respond by secreting soluble factors, including cytokines.8 DCs migrate to secondary lymphoid organs and are highly capable of activating naïve T cells, thus providing a key link in the induction of adaptive immunity (or in the absence of inflammation, the maintenance of tolerance). In both innate and adaptive responses, these cells seem to be context and/or subset dependent—they can be pro- or anti-inflammatory, and they can promote or suppress adaptive immune responses. DCs are ubiquitous, and they are found throughout the body in both lymphoid organs and peripheral tissues. They are adapted to fit the needs of the different organs in which they reside, but they are also recruited in inflammatory states, adhering as monocytes and differentiating into inflammatory DCs. Broadly speaking, DCs can be conventional dendritic cells (cDCs) or plasmacytoid DCs, with the majority of DCs within the kidney being cDCs. Traditionally, although recognized as imperfect, CD11c has been considered to be a marker of DCs, including in the kidney. Since the identification of DCs in the kidney, there have been a number of studies that show that CD11c+ renal cells can present antigen, and in disease, they are more active and present antigen more effectively in vivo.2,9,10 Several classifications of renal DCs have, however, highlighted the different subsets of renal DCs and the difficulties of using markers without functional and behavioral studies.11 In this issue of the JASN, Brähler et al.5 use fluorescent reporter mice in a series of substantial studies to further challenge the concept that intrarenal CD11c+ cells are predominantly DCs and advance our understanding of the nature of the renal mononuclear cells. Brähler et al.5 used CD11c+ reporter mice and reporter mice on the basis of the transcription factor ZBTB46 that is specific to cDCs in other tissues in mice.12 As previously established, they found that CD11cYFP+ cells were usually F4/80+ and also CD64+, whereas ZBTB46+ cells were largely negative for these markers.2,3 Although F4/80+CD64+CD11c+ cells could stimulate naïve T cells, cells that were CD11c+F4/80−CD64− were more efficient. Ex vivo multiphoton microscopy of thick sections of kidneys showed that the small, round, and more motile cells with limited dendrites were ZBTB46+, whereas the cells with more prominent probing processes were less motile and ZBTB46−. These patterns were supported by imaging mass spectrometry of kidney sections. Thus, by using ZBTB46 as the reference for what is a DC and by extension, what is a macrophage, Brähler et al.5 defined relatively sessile CD11c+ cells with spindly probing process as macrophages and small, round motile CD11c− cells as DCs. Studies on the functional role of these ZBTB46+ cells, focusing on the innate function of these cells, showed that they were proinflammatory. The model "nephrotoxic serum nephritis" was used, where an antirenal basement membrane antibody raised in sheep is injected into mice. Initially, injury is mediated by the transferred foreign antibody as an antibody (known as the heterologous phase), and DCs (systemic and renal) are also presenting the foreign sheep protein to naïve T cells. In a later phase of disease, effector T cells and mouse antibodies directed against the sheep globulin present in the kidney mediate injury (the autologous phase).13 Depletion of ZBTB46+ cells reduced albuminuria and limited the early, presumably innate influx of T cells. Later in the course of the model (14 days), renal function was improved, potentially reflecting lack of T cell priming by systemic DCs in addition to any effects mediated by renal DCs. It is unclear how depletion of cells clustering around interstitial vessels affects early glomerular injury, but imaging did report that ZBTB46+ cells were present in the interstitium in acute disease. DCs are extremely uncommon in normal glomeruli, although their numbers may increase in experimental inflammatory states.14 Pathologic albuminuria was the major early end point, and these proinflammatory innate effects may be a direct effect on the tubulointerstitium. Alternately, these effects might represent a form of tubuloglomerular feedback as suggested by previous work.15 Further studies used SNX22 reporter mice to define CD103+ DCs, showing similar localization to the ZBTB46+ cells. Studies in Batf3 deficient mice that lack CD103+ DCs confirmed the protective role for the CD103+ subset in this model, but unlike a previous report,16 their protective role was explained functionally by CD103+ DCs attenuating renal neutrophil recruitment. In contrast to CD103+ DCs, CD11b+ cells seem to be pathogenic in a variety of situations. A proportion of renal mononuclear phagocytes, both DCs and macrophages, expresses this marker, and in disease, inflammatory macrophages and DCs are derived from recruited inflammatory monocytes.4 What then are the roles of renal DCs? The answer is complex—their functions are context and subset dependent. The majority of studies, including the study by Brähler et al.,5 have focused on their innate roles. Subsets of renal mononuclear phagocytes, including both DCs and macrophages, can act as pro- or anti-inflammatory innate cells.4,8,17,18 In their roles as "professional" antigen presentation cells, renal mononuclear phagocytes likely help maintain tolerance to filtered antigenic peptides.19 They also sense "danger," and in inflammatory states, they both enhance local recognition of antigen in the tubulointerstitium and traffic to draining lymph nodes to present renal antigens to naïve T cells.10 The motility studies, showing that the small round DCs are more motile, whereas the more spindly cells are less so, are consistent with studies in other tissues (for example, the skin).20 However, migration of CD11c+ cells to the draining lymph node is not excluded: their numbers initially fall after immune stimuli.9 The functions of DCs can also be modulated by proximal tubular cells.21 This study's application of newer and more specific DC markers on the basis of ontogeny to redefine renal DC subsets may allow more accurate phenotyping and a more detailed understanding of their roles in future studies. The findings of Brähler et al.5 suggest further questions. Are these markers the new gold standard in defining a renal DC and a renal macrophage? Is function as a DC or a macrophage predetermined and fixed—or is a degree of plasticity, as proposed by several authors, still likely?18,22 Future studies in renal DCs and macrophages could ideally use reporter mice for behavior and localization in vivo and for cell surface markers and transcriptional profile studies ex vivo together with in vivo and ex vivo functional assessments of pro- or anti-inflammatory functions and antigen presentation. The study of Brähler et al.5 suggests that we should consider a new way of classifying renal DCs and macrophages. They lead us farther along the long and winding road in understanding the nature and function of DCs in the kidney. Such early translational research is essential if we are to be led to—and through—the door to more effective and targeted therapies for kidney disease. Disclosures None.