Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2011 May 1.
Published in final edited form as: Semin Nephrol. 2010 May;30(3):268–277. doi: 10.1016/j.semnephrol.2010.03.005

Macrophages, Dendritic cells and Kidney Ischemia-Reperfusion Injury

Li Li 1, Mark D Okusa 1
PMCID: PMC2904394  NIHMSID: NIHMS188223  PMID: 20620671

Abstract

Dendritic cells and macrophages are critical early initiators of innate immunity in the kidney and orchestrate inflammation subsequent to ischemia-reperfusion injury. They are the most abundant leukocyte present in the kidney, and they represent a heterogeneous population of cells that are capable of inducing ‘sterile’ inflammation following reperfusion directly through the production of proinflammatory cytokines and other soluble inflammatory mediators or indirectly through activation of effector T lymphocytes and nature killer T cells. In addition, recent studies indicate that kidney and immune cell microRNAs control gene expression and have the ability to regulate the initial inflammatory response to injury. Although dendritic cells and macrophages contribute to both innate and adaptive immunity and to injury and repair, this review will focus on the initial innate response to kidney ischemia-reperfusion injury.

Keywords: antigen presentation, leukocyte, innate immunity, inflammation

Introduction

Dendritic cells and macrophages play an important role in the innate and adaptive immune response of acute ischemia-reperfusion injury (IRI). In the kidney they reside in the interstitial extracellular compartment and are poised to interact with substances transported from the tubule lumen into peritubular capillaries 1, endogenous molecules released from parenchymal cells or exogenous invading organisms, or with resident or infiltrating immune cells including lymphocytes, nature killer T (NKT) cells, epithelial cells and fibroblasts. Electron microscopy has identified characteristics that may differentiate dendritic cells from macrophages. Dendritic cells are characterized by Birbeck granules, specialized compartments serving as reservoirs for antigen processing, and they have a greater density of mitochondria and rough endoplasmic reticulum, larger Golgi and fewer lysosomes 1 than macrophages. Dendritic cells and macrophages are key initiators, potentiators and effectors of innate immunity in kidney IRI and induce injury either through inflammatory signals to other effector cells or directly through the release of soluble mediators. The early immune response consists of activation of dendritic cells and macrophages that produce cytokines and chemokines leading to a prompt influx of leukocytes. In addition, dendritic cells, potent antigen presenting cells, contribute to the innate immune response by activating NKT cells and promoting inflammation. Following activation, macrophage and dendritic cell subpopulations subsequently contribute to the resolution of injury. Although often discussed as discrete cells, the heterogeneous population of antigen presenting cells represents a continuum from macrophages to dendritic cells 2 that contribute to both the early and late phases of kidney IRI 3,4 (Figure 1). Whereas the role of antigen presenting cells in the resolution of injury are described elsewhere in this series, this paper will focus on the early initiating events of kidney IRI for which macrophages and dendritic cells serve as catalysts for subsequent inflammation.

Figure 1. Heterogeneity of antigen presenting cells in the kidney.

Figure 1

Open in a new tab

Kidney section of the outer medulla from C57BL/6 background CX3CR1+/GFP mouse. GFP is expressed mainly on monocyte/macrophages and dendritic cells (green). Sections were also stained for MCH class II (PE-tagged IA-positive cells). High magnification of images of the kidney medulla viewed under a Zeiss LSM-510 confocal microscope showed CX3CR1-GFP+ cells in green and PE-tagged IA+ cells in red identifying dendritic cells.

Overview of acute kidney ischemia-reperfusion injury

The initial event leading to tissue injury in kidney IRI is the acute reduction of blood flow that produces hypoxia-induced vascular and tubular dysfunction. The S3 segment of the proximal tubule is located in the renal medulla and is particularly susceptible to injury in part due to the normally low ambient oxygen tension (PO2 of 5–20 mmHg) 5,6. Following reperfusion, various intracellular events occur that lead to cellular dysfunction, apoptosis and cell death (for reviews see 7-9). Mitochondria become swollen and fragmented with reduced membrane potential and generate reactive oxygen species and nitric oxide 10,11. Intracellular calcium accumulates 12,13 and membranes and lipids are damaged 14,15 whilst NF-κB signaling pathways 16 and poly(ADP-ribose) polymerase (PARP) are activated 17. Subsequent alterations in ultrafiltration coefficient, tubular obstruction and/or backleak reduce the glomerular filtration rate resulting in acute renal dysfunction. The innate immune system, leading to the activation of bone marrow-derived cells, endothelial cells and epithelial cells, significantly contributes to kidney IRI 3,18.

Inflammation in acute kidney ischemia-reperfusion injury

Inflammation is an important early event leading to intracellular responses that ultimately result in apoptosis and necrosis. Breakdown of the regulation of inflammatory responses results in tissue injury despite the concurrent activation of alternative pathways that eventually lead to remodeling and tissue repair. Thus, the involvement of the immune system in kidney IRI is very complex. Delineation of the orchestration of immune cells following kidney IRI has been made possible with the application of flow cytometry and the use of genetically modified mice, before which quantitative analysis relied primarily on immunohistochemical labeling of small samples of tissue. Using multi-color flow cytometry, a comprehensive profile of resident and infiltrating leukocytes following kidney IRI has been described 19. Resident kidney dendritic cells are the dominant leukocyte subset and are distributed throughout the whole kidney 19. Figure 2 illustrates the temporal profile of leukocyte trafficking following kidney IRI. The appearance in the kidneys of neutrophils and macrophages - components of the innate immune system - within 30 min following reperfusion, provides support for their pathogenic role in kidney IRI 19-21. CD4+ and CD8+ T cells and B220+ cells (B cells) also rapidly infiltrate the kidney within 30 min following reperfusion. Both neutrophil and macrophage infiltration peaks at 24-48 hours and remains elevated for at least 6 days following reperfusion injury. Although effective in eradicating pathogens, a consequence of such a stereotypical, generalized response is secondary tissue injury. Dendritic cells, neutrophils, phagocytic macrophages and lymphocytes participate in the early phase of kidney IRI as well as the late reparative phase. Using flow cytometry and immunofluorescence microscopy the kinetics of neutrophil migration from intravascular to interstitial compartments has been clearly demonstrated 22. In these studies neutrophils marginate and then transmigrate across the vascular wall into the surrounding interstitium where they damage tissue. The early activation of macrophages and dendritic cells leads to the infiltration of neutrophils with dendritic cell generation of IL-23 contributing to the activation of neutrophils and leading to the production of the proinflammatory cytokine IL-17 (L. Li and M.D. Okusa unpublished observations 2009). Thus, accumulating data suggest that dendritic cells and macrophages contribute early in the innate immune response to kidney IRI and promote neutrophil infiltration. However, while dendritic cells and macrophages contribute to kidney IRI, T regulatory (Tregs) cells have been shown to suppress the extent of kidney IRI through an IL-10 dependent mechanism 23.

Figure 2. Flow cytometric analysis of intrarenal leukocytes populations in kidney kidney ischemia/reperfusion injury.

Figure 2

Open in a new tab

Suspended kidney cells were stained and, by gating on the CD45+7AAD− live leukocyte population, F4/80+ macrophages were detected by flow cytometry. The profile of macrophage influx into kidneys in comparison to other leukocytes (as determined by flow cytometric analysis) following ischemia-reperfusion injury is shown in the early (0.5-24 hrs) and late (48-148 hrs) phases of reperfusion. GR-1, neutrophils; B220, B cells; CD4 and CD8, T cells; F4/80, macrophages.

The innate immune system has evolved as a host defense mechanism that recognizes microbial products. Toll-like receptors (TLRs) and a limited number of other receptors respond to highly conserved structures referred to as pathogen-associated molecular patterns (PAMPs), leading to a rapid and stereotypical response 24,25. Although this concept describes the initiation of inflammation following infections, similar processes that initiate inflammation are likely to occur in response to tissue trauma and autoimmune inflammation 26. A number of molecular patterns associated with release of endogenous cellular molecules, such as mammalian DNA, RNA, heat shock proteins, interferon-α, interleukin-1β, CD40-L, fibronectin fragments, modified low density lipoproteins (oxLDL), extracellular ATP and high mobility group box chromosomal protein 1 (HMGB1), may initiate the inflammatory responses of the TLR and NOD-like receptor (NLR) family of receptors 27 ‘Danger signals’ that permit rapid cellular communication are a key conceptual component of immune activation in both infection and sterile tissue injury. Activation of TLRs results in rapid changes in the expression of genes encoding cytokines, degradative enzymes and enzymes involved in the production of multiple low molecular weight inflammatory mediators 28. Once activated, an inflammatory and immune response leads to sequestration of leukocytes in inflamed sites, complement activation and eradication of pathogens through cytokines, complement/membrane attack complex and the actions of NKT cells 3,4,18.

Heterogeneity of kidney macrophages and dendritic cells

Blood monocytes are a heterogeneous cell population and are the precursors of tissue macrophages and dendritic cells (Figure 3). At least 2 distinct blood monocyte subsets are found in mice depending on the time they spend in the bloodstream 29-32. Monocyte subsets migrate into normal tissue and differentiate into ‘resident’ dendritic cells and macrophages 33,31, and they infiltrate inflamed tissue and differentiate into activated macrophages or dendritic cells 30. ‘Resident monocytes’ are characterized as CCR2−CX3CR1highGR-1−Ly6C−, whereas ‘inflammatory’ monocytes are defined as CCR2+CX3CR1lowGR-1+Ly6Chigh 30. Following tissue damage or infection, a coordinated multistep response is thought to occur involving the circulating ‘resident monocyte’ population that expresses LFA-1 and CX3CR1. These resident monocytes ‘patrol’ and monitor the endothelium of normal tissue and, following injury, rapidly migrate into the inflamed tissue where they differentiate into macrophages and initiate an early innate immune response 33.

Figure 3. Trafficking of monocytes in mice following kidney ischemia/reperfusion injury.

Figure 3

Open in a new tab

Bone marrow CD11b+Ly6Chigh monocyte/monocyte precursor egress to the blood circulation is CCR2-dependent. (a) Some of the Ly6Chigh monocytes lose their CCR2 and Ly6C expression and are further characterized as being CD62L−GR-1−CX3CR1high. (b) These ‘resident monocytes’ migrate to normal non-inflamed tissue rapidly after they are released in the blood and differentiate into tissue dendritic cells (DCs), which are CD11b+CD11c+IAhigh CD86+F4/80high (c) On the other hand, some of the monocytes continue to express CCR2+ and Ly6Chigh on the cell surface and are also CX3CR1lowGR-1intCD62L+. (d) These ‘inflammatory monocytes’ respond to the gradient of chemokines (e) released from kidneys following ischemia-reperfusion injury. In the injured tissue, the macrophages derived from ‘inflamed monocytes’ are characterized as being CD62L+Gr-1intLy6C+F4/80low. Infiltrating macrophages produce large amounts of pro-inflammatory cytokines, which are involved in tissue injury.

The prevailing microenvironment within the tissue plays a key role in determining macrophage phenotype. TNF-α, IL-4 and IL-15 skew monocyte differentiation towards dendritic cells 34-36 whereas IFN-γ and IL-6 direct monocyte differentiation towards macrophages 37,38. The macrophage phenotype switch occurs over time and parallels the course of inflammation or infection. Thus it is likely that the phenotype of macrophages and dendritic cells in inflamed tissues is the result of transmigration of cells derived from subsets of circulating monocyte as well as phenotypic changes of macrophages and dendritic cells made in response to cues within the local microenvironment.

Macrophage and dendritic cell trafficking in kidney ischemia-reperfusion

Given their diverse functions, macrophages might participate in early stages of injury or in the late stage repair process following kidney IRI. Monocytes/macrophages appear in the kidney within 1–5 days of IRI 39-42, as do macrophage-associated cytokines (e.g. IL-1, IL-6 and transforming growth factor-β [TGF-β]) 40 and the monocyte/macrophage chemoattractants interferon-gamma-inducible 10 kD protein (IP-10), monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein 2 (MIP-2) 43-45. Monocyte/macrophage migration into inflamed atherosclerotic vessels depends on CCR2, CCR5 and CX3CR1 46, and similarly migration of monocyte/macrophages in kidney IRI depends on CX3CR1 19,47 and CCR2 19. CCR2-deficient mice were protected from kidney IRI and this protection was associated with reduced macrophage infiltration 48. A causal relationship between CCR2+ monocyte/macrophages and tissue injury following kidney IRI was demonstrated by protection from injury and reduced monocyte infiltration into injured tissue following adoptive transfer of CCR2−/− monocytes to bone marrow ablated mice. In contrast, reconstitution with CCR2+/+ monocytes facilitated kidney macrophage infiltration and induced tissue injury. Therefore, ‘inflammatory monocyte’ migration into the reperfused kidney is, at least in part, CCR2-dependent and contributes to the pathogenesis of early inflammation in kidney IRI.

Fractalkine (CX3CL1) is a macrophage chemoattractant expressed on the surface of endothelial cells and is the ligand for the fractalkine receptor (CX3CR1). CX3CR1lowGR-1+CCR2+ subsets of monocytes are actively recruited to inflamed tissue whilst CX3CR1highGR-1−CCR2− subsets of monocytes migrate to uninjured tissue and differentiate into resident macrophages and dendritic cells 32. CX3CR1 deficiency (CX3CR1GFP/GFP mice) or treatment with a CX3CR1 blocking antibody 47 protected kidneys from IRI thereby indicating that CX3CR1 is a key signal that mediates infiltration of ‘inflammatory monocytes’ into injured kidneys following IRI.

Functional role of macrophages and dendritic cells in ischemia-reperfusion injury

Classic depletion and reconstitution studies have established the role of macrophages and dendritic cells in renal injury 49,50. For example, nitrogen mustard or anti-macrophage serum was used to abrogate injury in a model of glomerulonephritis with the protective effect being lost following the reconstitution of macrophages 50. Macrophage depletion using bisphosphonate clodronate (dichloromethylene bisphosphonate [Cl(2)MBP]) protected tissue from IRI 42,51, providing strong evidence for the participation of macrophages in the induction of injury following IRI. The role of dendritic cells can be assessed more specifically through the use of transgenic mice expressing the human diphtheria toxin receptor (DTR; human heparin binding epidermal growth factor-like growth factor [HB-EGF]) in CD11c+ cells (CD11c-DTR transgenic mouse) 52. Transgenic expression of the human DTR renders normally DT resistant murine cells DT sensitive. Using this inducible lineage ablation method, exposure of CD11c-DTR mice, to low dose DT will kill primarily CD11c+ DCs. Kidney CD11c+GFP+ DCs were efficiently depleted in CD11c-DTR/GFP mice by DT but not by mutant DT, as revealed by immunofluorescence studies (Fig. 4a). Kidney injury, as indicated by a rise in plasma creatinine (Fig. 4b) or H&E staining showing tubular cell necrosis (Fig. 4c), was significantly less in the CD11c-DTR/GFP mice that received DT treatment prior to IRI in comparison to control mutant DT treatment. The protective effect was not evident in DT- or mutant DT-treated wild-type control mice (Fig. 4b, c). Thus dendritic cells actively contribute to the early innate injurious response in kidney IRI.

Figure 4. Dendritic cells are important in the pathogenesis of kidney IRI.

Figure 4

Open in a new tab

(a) CD11c+GFP+ cells (arrows) in mouse kidney sections from CD11c-DTR/GFP mice (which express the human diphtheria toxin receptor (DTR) as a GFP fusion protein) were revealed immunohistochemically with GFP antibody (FITC fluorescence, green). Biologically inactive mutant DT had no effect on the number of GFP positive CD11c cells in the CD11c-DTR/GFP sham and IRI mouse kidneys. However there were significantly less GFP labeled cells in the sham and IRI kidneys of CD11c-DTR/GFP mice after administration of bioactive DT. Scale bar = 50 μM. (b) Plasma creatinine level was measured in wild-type (WT) and CD11c-DTR/GFP mice that received mutant (control) or bioactive DT (4 μg/g) 48 h prior to surgery. Values are mean ± SE; N=2-11; ***, P< 0.001. (c) H&E staining of kidneys from WT and CD11c-DTR/GFP mice reveals marked tubular injury in WT kidneys after IRI. Pretreatment with bioactive but not mutant DT prior to kidney IRI protected CD11c-DTR mouse kidneys from injury. Arrows indicate necrotic tubules. Scale bar = 100 μm. Data in (a) and (c) are representative of more than 3 experiments. Data from L. Li et al.19

Effector mechanisms of antigen presenting cells in kidney ischemia-reperfusion injury

Activation of NKT cells in kidney ischemia-reperfusion injury

Although CD4+ cells are known to contribute to kidney IRI, the antigen specific activation of T cells typically contributes to adaptive immunity and is a process not consistent with acute IRI that occurs within 24 hours. However, CD4+ T cells consist of functionally distinct subsets, including NKT cells that participate in innate immunity and could contribute to kidney IRI. CD4+ cells were found to infiltrate the kidney within 30 min following IRI (Figure 2), and IFN-γ producing CD1d-restricted NKT cells were identified early in kidney IRI. Furthermore, significant protection from kidney IRI was evident in mice administered a CD1d mAb which blocks the interaction between antigen presenting cells and NKT cells as well as mice deficient in NKT cells (Ja18−/−) 53. These studies suggest that the CD1d molecule expressed on kidney DCs can present endogenous glycolipid to NKT cells (signal 1) thereby stimulating CD40-CD40L interaction (signal 2) and cytokine (IL-12) production (signal 3) to promote the innate immune response 54. Activation of CD1d-restricted NKT cells also promotes IFN-γ producing GR-1+ neutrophil infiltration and tissue inflammation following kidney IRI 53.

Soluble mediators and phagocytosis in inflammation

Macrophages and dendritic cells are involved in antigen presentation and immunoregulation, and they express a large number of cell surface proteins that play an important role in the phagocytic function of these cells. Activation of macrophages and dendritic cells produces proinflammatory cytokines such as IL-1α, IL-6, IL-12, IL-18 and TNF-α via MyD-88 dependent or independent pathways. The observation that kidneys produce IL-1β and IL-18 following IRI55 suggests the potential involvement of the inflammasome, a multiprotein complex in macrophages and dendritic cells, in the inflammatory processes 56. NOD-like receptors (NLRs) possess pattern recognition receptors (PRR) and are important sensors of microbial products and other PAMPS. Once NLRs recognize microbial products or endogenous ‘danger signals’, this leads to activation of caspase 1 and assembly of the inflammasome. Caspase 1 then promotes the maturation of the inflammatory cytokines IL-1β and IL-18 57. No studies to date have examined the role of inflammasomes in acute kidney IRI.

Insights into the mechanisms by which macrophages induce tissue injury may be gained from studies of their role in infection. The antimicrobial action of macrophages is mediated thorough oxidative mechanisms including the production of reactive oxygen intermediates by phagocyte oxidase (phox) and reactive nitrogen intermediates (RNI) generated by inducible nitric oxide synthase (iNOS; NOS2) 58,59. Macrophages also exert antimicrobial actions via a phox- and NOS2-independent mechanism 60. In addition, non-oxidative antimicrobial actions by macrophages may induce tissue injury. Macrophage specific metalloelastase (MME) is involved in remodeling of the extracellular matrix associated with inflammation and the repair process 61. Macrophages also generate matrix metalloproteinase 12 (MMP12), a powerful enzyme that adheres to the bacterial wall to mediate bacterial killing but also degrades matrix proteins during inflammation. Thus propensity of macrophages to elaborate these effective mediators for bacterial killing may also lead to tissue injury following the ‘sterile’ inflammatory response that follows kidney IRI.

Macrophage and dendritic cell microRNAs (miRNAs) in inflammation

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level by either degradation or translational repression of a target mRNA. They play a critical role in gene regulation through their stability and translation in the kidney 63. For example, uremia associated with acute kidney injury suppressed pro-inflammatory cytokine mRNA levels and altered the expression of least 69 miRNAs 64. A number of miRNAs contribute to the maturation of macrophages via TLR signaling. TLR and IFN-β stimulate production of miRNA by the NF-κB and Jun N-terminal kinase pathway. TNF-α is a target gene of miR-125b and downregulation of miR125b is required to ensure that a proper inflammatory response is generated by macrophages in response to microbial stimulation 65. The miRNA-146a reduces the expression of IRAK1 and TRAF6 of the TLR signaling cascade and thus acts to provide negative feedback to prevent excessive inflammation 66. Several TLR ligands increase miR-155 expression via the MyD88 or TRIF signal pathway and miR-155 is upregulated by LPS and promotes TNF-α production from macrophages 67. Furthermore, miR-155 also regulates DC antigen presentation and costimulation activity with DCs from miR-155 knockout mice being unable to induce efficient T cell activation 66. These studies demonstrate that a variety of miRNAs act to regulate dendritic cell and macrophage function and may thus participate in modulating tissue injury following kidney IRI.

Conclusion

Dendritic cells and macrophages are the most abundant leukocytes expressed in the normal kidney. They represent a continuum of cell phenotype in which macrophages, which have poor antigen processing and presentation properties, produce proinflammatory cytokines and soluble mediators that contribute to innate immunity in kidney IRI. At the other end of the spectrum are dendritic cells, which upon activation, function in processing and presenting antigen to effector T cells. Presentation of endogenous glycolipid to NKT cells following kidney IRI initiates injurious responses. The early activation of dendritic cells and macrophages orchestrates an immune response that leads to ‘sterile’ inflammation and associated tissue damage and these immune cells will likely serve as important therapeutic targets in the future.

Acknowledgments

The authors acknowledge Ms. Liping Huang, Hong Ye (Department of Medicine, University of Virginia) for generation of much for the data for this manuscript and Dr. Diane Rosin (Department of Pharmacology, University of Virginia) for helpful discussions and careful reading of the manuscript.

Supported in part by funds from NIH RO1DK56223, RO1DK62324, Genzyme (Genzyme Renal Innovations Program) and an American Heart Associate National Scientist Development Grant 0835258N.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.Kaissling B, Le Hir M. Characterization and distribution of interstitial cell types in the renal cortex of rats. Kidney Int. 1994;45(3):709–20. doi: 10.1038/ki.1994.95. [DOI] [PubMed] [Google Scholar]
  • 2.Ferenbach D, Hughes J. Macrophages and dendritic cells: what is the difference? Kidney Int. 2008;74(1):5–7. doi: 10.1038/ki.2008.189. [DOI] [PubMed] [Google Scholar]
  • 3.Kinsey GR, Li L, Okusa MD. Inflammation in acute kidney injury. Nephron Exp Nephrol. 2008;109(4):e102–7. doi: 10.1159/000142934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Li L, Okusa MD. Blocking the Immune respone in ischemic acute kidney injury: the role of adenosine 2A agonists. Nature Clinical Practice Nephrology. 2006;2:432–44. doi: 10.1038/ncpneph0238. [DOI] [PubMed] [Google Scholar]
  • 5.Mason J, Torhorst J, Welsch J. Role of the medullary perfusion defect in the pathogenesis of ischemic renal failure. Kidney Int. 1984;26:283–93. doi: 10.1038/ki.1984.171. [DOI] [PubMed] [Google Scholar]
  • 6.Brezis M, Rosen SN, Epstein FH. The pathophysiological implications of medullary hypoxia. Am J Kid Dis. 1989;13(3):253–8. doi: 10.1016/s0272-6386(89)80062-9. [DOI] [PubMed] [Google Scholar]
  • 7.Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med. 1996;334:1448–60. doi: 10.1056/NEJM199605303342207. [DOI] [PubMed] [Google Scholar]
  • 8.Bonventre JV, Weinberg JM. Recent advances in the pathophysiology of ischemic acute renal failure. J Am Soc Nephrol. 2003;14(8):2199–210. doi: 10.1097/01.asn.0000079785.13922.f6. [DOI] [PubMed] [Google Scholar]
  • 9.Schrier RW, Wang W, Poole B, Mitra A. Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J Clin Invest. 2004;114(1):5–14. doi: 10.1172/JCI22353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Plotnikov EY, Kazachenko AV, Vyssokikh MY, Vasileva AK, Tcvirkun DV, Isaev NK, et al. The role of mitochondria in oxidative and nitrosative stress during ischemia/reperfusion in the rat kidney. Kidney Int. 2007;72(12):1493–502. doi: 10.1038/sj.ki.5002568. [DOI] [PubMed] [Google Scholar]
  • 11.Brooks C, Wei Q, Cho SG, Dong Z. Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. J Clin Invest. 2009;119(5):1275–85. doi: 10.1172/JCI37829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Arnold PE, Van Putten VJ, Lumlertgul D, Burke TJ, Schrier RW. Adenine nucleotide metabolism and mitochondrial Ca2+ transport following renal ischemia. Am J Physiol. 1986;250(2 Pt 2):F357–63. doi: 10.1152/ajprenal.1986.250.2.F357. [DOI] [PubMed] [Google Scholar]
  • 13.Arnold PE, Lumlertgul D, Burke TJ, Schrier RW. In vitro versus in vivo mitochondrial calcium loading in ischemic acute renal failure. Am J Physiol. 1985;248(6 Pt 2):F845–50. doi: 10.1152/ajprenal.1985.248.6.F845. [DOI] [PubMed] [Google Scholar]
  • 14.Jo SK, Bajwa A, Awad AS, Lynch KR, Okusa MD. Sphingosine-1-phosphate receptors: biology and therapeutic potential in kidney disease. Kidney Int. 2008;73(11):1220–30. doi: 10.1038/ki.2008.34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Zager RA, Iwata M, Conrad DS, Burkhart KM, Igarashi Y. Altered ceramide and sphingosine expression during the induction phase of ischemic acute renal failure. Kidney Int. 1997;52(1):60–70. doi: 10.1038/ki.1997.304. [DOI] [PubMed] [Google Scholar]
  • 16.Chatterjee PK, Brown PA, Cuzzocrea S, Zacharowski K, Stewart KN, Mota Filipe H, et al. Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat. Kidney Int. 2001;59(6):2073–83. doi: 10.1046/j.1523-1755.2001.00722.x. [DOI] [PubMed] [Google Scholar]
  • 17.Zheng J, Devalaraja-Narashimha K, Singaravelu K, Padanilam BJ. Poly (ADP-ribose) polymerase-1 gene ablation protects mice from ischemic renal injury. Am J Physiol. Renal Physiol. 2005;288(2):F387–98. doi: 10.1152/ajprenal.00436.2003. [DOI] [PubMed] [Google Scholar]
  • 18.Jang HR, Rabb H. The innate immune response in ischemic acute kidney injury. Clin Immunol. 2009;130(1):41–50. doi: 10.1016/j.clim.2008.08.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Li L, Huang L, Sung SS, Vergis AL, Rosin DL, Rose CE, Jr., et al. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury. Kidney Int. 2008:1509–11. doi: 10.1038/ki.2008.500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Rabb H. The T cell as a bridge between innate and adaptive immune systems: implications for the kidney. Kidney Int. 2002;61(6):1935–46. doi: 10.1046/j.1523-1755.2002.00378.x. [DOI] [PubMed] [Google Scholar]
  • 21.Rodriguez-Iturbe B, Pons H, Herrera-Acosta J, Johnson RJ. Role of immunocompetent cells in non-immune renal diseases. Kidney Int. 2001;59(5):1626–40. doi: 10.1046/j.1523-1755.2001.0590051626.x. [DOI] [PubMed] [Google Scholar]
  • 22.Awad AS, Rouse M, Huang L, Vergis AL, Reutershan J, Cathro HP, et al. Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury. Kidney Int. 2009:689–98. doi: 10.1038/ki.2008.648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Kinsey GR, Sharma R, Huang L, Li L, Vergis AL, Ye H, et al. Regulatory T Cells Suppress Innate Immunity in Kidney Ischemia-Reperfusion Injury. J Am Soc Nephrol. 2009;20(8):1744–53. doi: 10.1681/ASN.2008111160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Anders HJ, Banas B, Schlondorff D. Signaling danger: toll-like receptors and their potential roles in kidney disease. J Am Soc Nephrol. 2004;15(4):854–67. doi: 10.1097/01.asn.0000121781.89599.16. [DOI] [PubMed] [Google Scholar]
  • 25.Janeway CA, Jr., Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197–216. doi: 10.1146/annurev.immunol.20.083001.084359. [DOI] [PubMed] [Google Scholar]
  • 26.Matzinger P. The danger model: a renewed sense of self. Science. 2002;296(5566):301–5. doi: 10.1126/science.1071059. [DOI] [PubMed] [Google Scholar]
  • 27.Zhang X, Mosser DM. Macrophage activation by endogenous danger signals. J Pathol. 2008;214(2):161–78. doi: 10.1002/path.2284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Han J, Ulevitch RJ. Limiting inflammatory responses during activation of innate immunity. Nat Immunol. 2005;6(12):1198–205. doi: 10.1038/ni1274. [DOI] [PubMed] [Google Scholar]
  • 29.Wilson HM, Walbaum D, Rees AJ. Macrophages and the kidney. Curr Opin Nephrol Hypertens. 2004;13(3):285–90. doi: 10.1097/00041552-200405000-00004. [DOI] [PubMed] [Google Scholar]
  • 30.Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19(1):71–82. doi: 10.1016/s1074-7613(03)00174-2. [DOI] [PubMed] [Google Scholar]
  • 31.Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR, et al. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science. 2006;311(5757):83–7. doi: 10.1126/science.1117729. [DOI] [PubMed] [Google Scholar]
  • 32.Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5(12):953–64. doi: 10.1038/nri1733. [DOI] [PubMed] [Google Scholar]
  • 33.Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science. 2007;317(5838):666–70. doi: 10.1126/science.1142883. [DOI] [PubMed] [Google Scholar]
  • 34.Dauer M, Obermaier B, Herten J, Haerle C, Pohl K, Rothenfusser S, et al. Mature dendritic cells derived from human monocytes within 48 hours: a novel strategy for dendritic cell differentiation from blood precursors. J Immunol. 2003;170(8):4069–76. doi: 10.4049/jimmunol.170.8.4069. [DOI] [PubMed] [Google Scholar]
  • 35.Mohamadzadeh M, Berard F, Essert G, Chalouni C, Pulendran B, Davoust J, et al. Interleukin 15 skews monocyte differentiation into dendritic cells with features of Langerhans cells. J Exp Med. 2001;194(7):1013–20. doi: 10.1084/jem.194.7.1013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Chomarat P, Dantin C, Bennett L, Banchereau J, Palucka AK. TNF skews monocyte differentiation from macrophages to dendritic cells. J Immunol. 2003;171(5):2262–9. doi: 10.4049/jimmunol.171.5.2262. [DOI] [PubMed] [Google Scholar]
  • 37.Delneste Y, Charbonnier P, Herbault N, Magistrelli G, Caron G, Bonnefoy JY, et al. Interferon-gamma switches monocyte differentiation from dendritic cells to macrophages. Blood. 2003;101(1):143–50. doi: 10.1182/blood-2002-04-1164. [DOI] [PubMed] [Google Scholar]
  • 38.Chomarat P, Banchereau J, Davoust J, Palucka AK. IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol. 2000;1(6):510–4. doi: 10.1038/82763. [DOI] [PubMed] [Google Scholar]
  • 39.Ysebaert DK, De Greef KE, Vercauteren SR, Ghielli M, Verpooten GA, Eyskens EJ, et al. Identification and kinetics of leukocytes after severe ischaemia/reperfusion renal injury. Nephrol Dial Transplant. 2000;15(10):1562–74. doi: 10.1093/ndt/15.10.1562. [DOI] [PubMed] [Google Scholar]
  • 40.Takada M, Nadeau KC, Shaw GD, Maruette KA, Tilney NL. The cytokine adhesion molecule cascade in ischemia/repefusion injury of the rat kidney. J Clin Invest. 1997;99:2682–90. doi: 10.1172/JCI119457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Persy VP, Verhulst A, Ysebaert DK, De Greef KE, De Broe ME. Reduced postischemic macrophage infiltration and interstitial fibrosis in osteopontin knockout mice. Kidney Int. 2003;63(2):543–53. doi: 10.1046/j.1523-1755.2003.00767.x. [DOI] [PubMed] [Google Scholar]
  • 42.Day YJ, Huang L, Ye H, Linden J, Okusa MD. Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages. Am J Physiol Renal Physiol. 2005;288(4):F722–31. doi: 10.1152/ajprenal.00378.2004. [DOI] [PubMed] [Google Scholar]
  • 43.Day Y-J, Huang L, McDuffie MJ, Rosin DL, Ye H, Chen JF, et al. Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow-derived cells. J Clin Invest. 2003;112(6):883–91. doi: 10.1172/JCI15483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Lemay S, Rabb H, Postler G, Singh AK. Prominent and sustained up-regulation of gp130-signaling cytokines and the chemokine MIP-2 in murine renal ischemia-reperfusion injury. Transplantation. 2000;69(5):959–63. doi: 10.1097/00007890-200003150-00049. [DOI] [PubMed] [Google Scholar]
  • 45.Takada M, Chandraker A, Nadeau KC, Sayegh MH, Tilney NL. The role of the B7 costimulatory pathway in experimental cold ischemia/reperfusion injury. J Clin Invest. 1997:1199–203. doi: 10.1172/JCI119632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest. 2007;117(1):185–94. doi: 10.1172/JCI28549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Oh DJ, Dursun B, He Z, Lu L, Hoke TS, Ljubanovic D, et al. Fractalkine receptor (CX3CR1) inhibition is protective against ischemic acute renal failure in mice. Am J Physiol Renal Physiol. 2008;294(1):F264–71. doi: 10.1152/ajprenal.00204.2007. [DOI] [PubMed] [Google Scholar]
  • 48.Furuichi K, Wada T, Iwata Y, Kitagawa K, Kobayashi K, Hashimoto H, et al. CCR2 Signaling Contributes to Ischemia-Reperfusion Injury in Kidney. J Am Soc Nephrol. 2003;14(10):2503–15. doi: 10.1097/01.asn.0000089563.63641.a8. [DOI] [PubMed] [Google Scholar]
  • 49.Holdsworth SR, Neale TJ, Wilson CB. Abrogation of macrophage-dependent injury in experimental glomerulonephritis in the rabbit. Use of an anti-macrophage serum. J Clin Invest. 1981;68(3):686–98. doi: 10.1172/JCI110304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Holdsworth SR, Neale TJ. Macrophage-induced glomerular injury. Cell transfer studies in passive autologous antiglomerular basement membrane antibody-initiated experimental glomerulonephritis. Lab Invest. 1984;51(2):172–80. [PubMed] [Google Scholar]
  • 51.Jo SK, Sung SA, Cho WY, Go KJ, Kim HK. Macrophages contribute to the initiation of ischaemic acute renal failure in rats. Nephrol Dial Transplant. 2006;21(5):1231–9. doi: 10.1093/ndt/gfk047. [DOI] [PubMed] [Google Scholar]
  • 52.Buch T, Heppner FL, Tertilt C, Heinen TJ, Kremer M, Wunderlich FT, et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat Methods. 2005;2(6):419–26. doi: 10.1038/nmeth762. [DOI] [PubMed] [Google Scholar]
  • 53.Li L, Huang L, Sung SJ, Lobo PI, Brown MG, Gregg RK, et al. NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury. J Immunol. 2007;178(9):5899–911. doi: 10.4049/jimmunol.178.9.5899. [DOI] [PubMed] [Google Scholar]
  • 54.Hayakawa Y, Takeda K, Yagita H, Van Kaer L, Saiki I, Okumura K. Differential regulation of Th1 and Th2 functions of NKT cells by CD28 and CD40 costimulatory pathways. J Immunol. 2001;166(10):6012–8. doi: 10.4049/jimmunol.166.10.6012. [DOI] [PubMed] [Google Scholar]
  • 55.Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS, Dinarello CA, et al. Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest. 2001 May;107(9):1145–52. doi: 10.1172/JCI12089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Mariathasan S, Monack DM. Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol. 2007;7(1):31–40. doi: 10.1038/nri1997. [DOI] [PubMed] [Google Scholar]
  • 57.Ogura Y, Sutterwala FS, Flavell RA. The inflammasome: first line of the immune response to cell stress. Cell. 2006;126(4):659–62. doi: 10.1016/j.cell.2006.08.002. [DOI] [PubMed] [Google Scholar]
  • 58.Nathan CF, Hibbs JB., Jr Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol. 1991;3(1):65–70. doi: 10.1016/0952-7915(91)90079-g. [DOI] [PubMed] [Google Scholar]
  • 59.Nathan CF. Mechanisms of macrophage antimicrobial activity. Trans R Soc Trop Med Hyg. 1983;77(5):620–30. doi: 10.1016/0035-9203(83)90190-6. [DOI] [PubMed] [Google Scholar]
  • 60.Shiloh MU, MacMicking JD, Nicholson S, Brause JE, Potter S, Marino M, et al. Phenotype of mice and macrophages deficient in both phagocyte oxidase and inducible nitric oxide synthase. Immunity. 1999;10(1):29–38. doi: 10.1016/s1074-7613(00)80004-7. [DOI] [PubMed] [Google Scholar]
  • 61.Shipley JM, Wesselschmidt RL, Kobayashi DK, Ley TJ, Shapiro SD. Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc Natl Acad Sci USA. 1996;93(9):3942–6. doi: 10.1073/pnas.93.9.3942. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Houghton AM, Hartzell WO, Robbins CS, Gomis-Ruth FX, Shapiro SD. Macrophage elastase kills bacteria within murine macrophages. Nature. 2009;460(7255):637–41. doi: 10.1038/nature08181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Saal S, Harvey SJ. MicroRNAs and the kidney: coming of age. Curr Opin Nephrol Hypertens. 2009;18(4):317–23. doi: 10.1097/MNH.0b013e32832c9da2. [DOI] [PubMed] [Google Scholar]
  • 64.Zager RA, Johnson AC, Lund S. Uremia Impacts Renal Inflammatory Cytokine Gene Expression in the Setting of Experimental Acute Kidney Injury. Am J Physiol Renal. Physiol. 2009;297(4):F961–70. doi: 10.1152/ajprenal.00381.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Bi Y, Liu G, Yang R. MicroRNAs: novel regulators during the immune response. J Cell Physiol. 2009;218(3):467–72. doi: 10.1002/jcp.21639. [DOI] [PubMed] [Google Scholar]
  • 66.Lu LF, Liston A. MicroRNA in the immune system, microRNA as an immune system. Immunology. 2009;127(3):291–8. doi: 10.1111/j.1365-2567.2009.03092.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci USA. 2007;104(5):1604–9. doi: 10.1073/pnas.0610731104. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES