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The Renal Mononuclear Phagocytic System

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The Renal Mononuclear Phagocytic System BRIEF REVIEW www.jasn.org The Renal Mononuclear Phagocytic System † ‡ Peter J. Nelson,* Andrew J. Rees, Matthew D. Griffin, Jeremy Hughes,¶ Christian Kurts,§ and Jeremy Duffield* *University of Washington, Seattle, Washington; †Medical University of Vienna, Vienna, Austria; ‡National University of Ireland, Galway, Ireland; ¶University of Edinburgh, Edinburgh, United Kingdom; and §University Clinic of Bonn, Bonn, Germany ABSTRACT The renal mononuclear phagocytic system, conventionally composed of macro- resident Mø because of F4/80 expres- phages (Mø) and dendritic cells (DCs), plays a central role in health and disease of sion.8–10 In addition, rare MHC class II+ the kidney. Overlapping definitions of renal DCs and Mø, stemming from historically globular Mø were identified in the glo- separate research tracks and the lack of experimental tools to specifically study the merulus11,12 and subcapsular and periar- roles of these cells in vivo, have generated confusion and controversy, however, terial connective tissue.13,14 Subsequently, regarding their immunologic function in the kidney. This brief review provides an however, multicolor flow cytometry re- appraisal of the current state of knowledge of the renal mononuclear phagocytic vealed substantial overlap and heteroge- system interpreted from the perspective of immunologic function. Physical charac- neity in expression of historically defined teristics, ontogeny, and known functions of the main subsets of renal mononuclear Mø (CD11b, F4/80, and CD68) and DC phagocytes as they relate to homeostasis, surveillance against injury and infection, (CD11c, MHC II, and CD80/86) markers and immune-mediated inflammatory injury and repair within the kidney are de- by interstitial rMoPh.15–19 Along with scribed. Gaps and inconsistencies in current knowledge are used to create a road- similar descriptions in normal human map of key questions to be answered in future research. kidney,20–22 these studies established the predominant rMoPh at steady state as J Am Soc Nephrol 23: 194–203, 2012. doi: 10.1681/ASN.2011070680 networked, dendritiform, interstitial cells that coexpress multiple markers previously thought to segregate Mø The mononuclear phagocytic system in additional and at times, overlapping from DCs. Hence, many investigators, nonlymphoid organs such as the kidney functional properties that extend be- whether originating from Mø or DC dis- is composed of diverse subsets of bone yond these classic paradigms. Further- ciplines, were unknowingly studying the marrow–derived macrophages (Mø) more, similar to mononuclear phagocytes same predominant rMoPh, while often and dendritic cells (DCs).1 Mø are de- in skin, lung, and gut, the predominant, neglecting knowledge from the other dis- fined as tissue-resident phagocytic cells resident renal mononuclear phagocytes cipline. As a result, the use of markers as that contribute to steady-state tissue ho- (rMoPh) simultaneously express markers surrogates for Mø or DC functions within meostasis by clearing apoptotic material traditionally associated with either Mø or the renal mononuclear phagocytic system and producing growth factors. During DCs.4–7 Indeed, as discussed below, many (Table 1) is increasingly questioned.22 infection, they perform antimicrobial ef- research groups have characterized these This debate has also been heightened by fector functions such as phagocytosis rMoPh for over three decades as either lack of specificity of reagents commonly and production of toxic metabolites Mø or DCs, despite growing evidence of used to induce loss of function of DCs or and proinflammatory cytokines.1,2 phenotypic and functional overlap, Mø (Table 2). DCs, however, are defined primarily by creating a barrier to cohesive progress in the specialized functions of antigen pre- the field. Published online ahead of print. Publication date sentation and regulation of immune Knowledge of rMoPh began with available at www.jasn.org. effector cells. Classically, DCs collect groundbreaking studies in normal kid- antigenic material in tissues and then neys of mice and rats that identified Correspondence: Dr. Peter J. Nelson, Division of Nephrology and Kidney Research Institute, Health migrate to lymph nodes for the purpose abundant dendritiform cells within the Sciences Center, Room BB1259, 1959 NE Pacific of presenting antigen to naïve T cells.1,3 renal interstitium. These cells were des- Street, Seattle, WA 98195. Email: [email protected] As summarized in Table 1, however, ignated antigen-presenting DCs on the Copyright © 2012 by the American Society of Mø and DCs within the kidney exhibit basisofMHCclassIIexpression8,9 or Nephrology 194 ISSN : 1046-6673/2302-194 J Am Soc Nephrol 23: 194–203, 2012 www.jasn.org BRIEF REVIEW Table 1. Distinct and shared functions of macrophages and dendritic cells Transgene reporters of cx3cr1 (CX3CR1) in the kidney and csf1r (CD115) fate map over 90% of Mø rMoPh within the kidney at steady classic functions state.17,18,33 The large majority of + phagocytosis of tissue debris and pathogens CX3CR1 cells is dendritiform rMoPh, mediation of tissue injury and disease progression which form a contiguous network a activated phenotypes exhibit distinct polarized functions throughout the entire renal interstitium contemporary additions of mice, lining the microvascular, peritub- phagocytosis to remodel matrix ular, and periglomerular spaces.17,33,34 support for nephrogenesis and cell fate decisions These predominant rMoPh are definable paracrine role in angiogenesis and epithelial regeneration fi + + fi by a marker pro le: CD11b MHCII polarized function can be brogenic + +/– +/– – potent source of chemokines and cytokinesa CX3CR1 CD11c F4/80 CD103 + mediate anti-inflammatory/immunosuppressive effects through innate responsesa (Figure 1, CD11b rMoPh), which is DCs similar to that of interstitial CD11b-like classic functions DC and tissue macrophages described in phagocytosis of antigen in kidney other nonlymphoid tissues.6,7,16–18 migration to renal lymph nodes Among this CD11b+ rMoPh subset, the antigen presentation to T lymphocytes reported frequency of expression of contemporary additions CD11c (either with or without F4/80 fi antigen presentation within the kidney to restimulate or modify in ltrating T lymphocytes coexpression) has varied between 40% mediate anti-inflammatory/immunosuppressive effects through innate responses and and 90%,15–17,35 indicating that addi- modulation of T lymphocytes (peripheral tolerance)a activated phenotypes exhibit distinct polarized functionsa tional phenotypic characterization of potent source of chemokines and cytokinesa these cells is yet required. In addition, aOverlapping functions. F4/80 is reportedly expressed preferen- tially by medullary rMoPh at steady state.10,17 This ambiguity resulting from con- phenotypes.30–32 In light of these shifting The second definable rMoPh subset, ventional nomenclature, now recognized paradigms, we reappraise here the cur- representing #5% of steady-state in- and intensely debated for the mono- rent knowledge of the renal mononuclear terstitial rMoPh, exhibits the surface 5 2 + – nuclear phagocytic system in general, phagocytic system. We focus on identi- phenotype CD11b MHCII CX3CR1 2 dictates that functional properties are fying gaps and inconsistencies in our CD11c+F4/80 CD103+ (Figure 1, CD103+ required to properly characterize the re- understanding of the ontogeny and func- rMoPh) and is, therefore, not visible in 1 18 nal mononuclear phagocytic system. tion of rMoPh in surveillance, tolerance, CX3CR1-GFP reporter mice. The func- Studies on whether the predominant in- and tissue cytoprotection during steady tion of this second subset in the kidney terstitial rMoPh isolated from kidneys state, as well as immunity, tissue injury, is unknown at present, but similar cells perform like splenic DCs by presenting and repair associated with inflammation. exist in skin, lung, and intestine where antigen and activating naïve T lympho- The emerging role for plasticity within they perform specialized functions, in- cytes or like peritoneal Mø by killing the renal mononuclear phagocytic sys- cluding cross-presentation and induction phagocytosed microbes showed the for- tem is also discussed. Notably, knowl- of regulatory T cells.1,4,6,18,36 Plasmacytoid mer function.15 This finding supports edge of these topics has come primarily DCs, which differ ontogenically, func- other reports suggesting migratory and by studying the mouse as a model organ- tionally, and phenotypically from CD11b+ phagocytic properties more typical of ism, and translation to humans, which rMoPh and CD103+ rMoPh, are difficult DCs.16,23 However, these early studies has been limited,20,21 remains an impor- to detect in normal mouse and human could not anticipate the multitude of tant goal. kidneys and may be absent.20,21 CD11b+ additional Mø and DC functions now rMoPh within normal glomeruli are assigned to the renal mononuclear phago- scarce, more globular-shaped, and cytic system24–30 or the fact that functional ONTOGENY OF MONONUCLEAR seem to lack CD11c and F4/80.15,19,37 plasticity—rather than dichotomy— PHAGOCYTES OF THE KIDNEY The rMoPh of normal human kidneys might exist depending on cues provided IN STEADY STATE show generally similar anatomic distribu- to rMoPh from the environment.22,29,30 tion and population heterogeneity,20,21 Moreover, the renal mononuclear phago- During the past 10 years, studies of specific but not all murine markers (F4/80 and cytic system at steady state changes dra- transgene
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