Innate pathogen recognition in the kidney: Toll-like receptors, NOD-like receptors, and RIG-like helicases

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1 BACTERIAL WALL COMPONENTS A group of cell surface TLRs and cytosolic NLRs recognize bacterial cell wall components (Table 1). A major cell wall component of all bacteria is peptidoglycan (PG), whereas lipoproteins and lipoteichoic acid are specific to Grampositive bacteria, and lipopolysaccharide (LPS) is specific for Gram-negative bacteria. LPS TLR4: The lipid core of LPS is a potent immunostimulatory cell wall component of Gram-negative bacteria. The LPS and soluble LPS-binding protein complex exposes LPS to CD14, MD-2 and the extracellular domain of TLR4 at the outer cell membrane. 2 Most cell types express TLR4 and respond to LPS. Outside-in signaling recruits cytosolic adapter molecules, which interact with their toll-interleukin 1 receptor (TIR) domain with the intracellular TIR domain of TLR4. 3 TLR4 can activate both the myeloid differentiation primary-response protein (MyD)-88- (tumor necrosis factor receptor associated factor (TRAF)-6, IL-1 receptor-associated kinase-1, interferon regulatory factor (IRF)-5, nuclear factorhttp:// & 2007 International Society of Nephrology mini review Innate pathogen recognition in the kidney: Toll-like receptors, NOD-like receptors, and RIG-like helicases H-J Anders 1 1 Department of Nephrology, Medical Policlinic, University of Munich, Munich, Germany How do infections trigger or aggravate renal pathology? The discovery of the toll-like receptors, and more recently, the retinoic-acid-inducible protein-like helicases and the nucleotide-binding oligomerization domain-like receptors may offer new concepts to answer this question. Common pathogen-associated molecules are recognized by these receptors in several cellular compartments of immune cells and non-immune cells inside the kidney. This article summarizes ligand receptor interactions and their known or potential significance in kidney diseases. Kidney International (2007) 72, ; doi: /sj.ki ; published online 25 July 2007 KEYWORDS: infection; inflammation; glomerulonephritis; kidney disease; interferon Correspondence: H-J Anders, Division of Nephrology, Medizinische Poliklinik der LMU, Campus Juuenstadt, Pettenkoferstr. 8a, Munich, Germany. hjanders@med.uni-muenchen.de Received 2 May 2007; revised 13 June 2007; accepted 19 June 2007; published online 25 July 2007 Infections cause many types of kidney diseases, directly or indirectly, and in both disease entities, host defense involves immunity-mediated pathology. What are the molecular mechanisms that mediate pathogen recognition and immunity-related renal damage? Why do some but not all microbes trigger immunity? Is pathogen recognition restricted to immune cells or do renal cells also contribute to this phenomenon? Which molecules recognize different classes of pathogens like bacteria or viruses and what is the evidence that single pathogen recognition molecules have a crucial role in distinct types of kidney disease? The understanding of innate pathogen recognition has been stimulated by the discovery of the human toll-like receptor (TLR) family 13 years ago. Since 2004 when we first reviewed the potential roles of TLRs in kidney disease, the evolving data propose novel disease concepts. Furthermore, the subsequent discovery of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family and the retinoic-acid-inducible protein (RIG)-like helicases (RLH) has broadened the view of how innate immunity assures pathogen recognition in different cellular compartments. 1 This review provides an update on the role of the recognition of pathogen-associated molecules in kidney diseases and discusses future perspectives in this field. Kidney International (2007) 72,

2 m i n i r e v i e w H-J Anders: Pathogen recognition in the kidney Table 1 Pathogen-associated molecules and innate pathogen recognition receptors Pathogen component Molecular pattern Toll-like receptor RIG-like helicase NOD-like receptor Bacterial wall All bacteria Peptidoglycan TLR2 NOD1, NOD2 Gram bacteria Lipopolysaccharide TLR4 Gram+ bacteria Triacyl lipopeptides TLR1-TLR2 Lipoteichoic acid TLR2-TLR6 Diacyl lipopeptides TLR2-TLR6 Porins TLR2 Mycobacteria Lipoarabinomannan TLR2 Triacyl lipopeptides TLR1-TLR2 Microbial or viral nucleic acids DNA CpG-DNA TLR9 dsdna? RNA dsrna TLR3 MDA5, RIG-I ssrna TLR7, TLR8 3P-RNA RIG-I Other pathogen components Flagella Flagellin TLR5 NAIP5, IPAF Uropathogenic E. coli? mtlr11 Viral envelope proteins RSV envelope protein TLR4 Measle virus hemagglutinin TLR2 CMV, HSV1 proteins TLR2 Fungal cell wall Candida phospholipomannan TLR2 Candida mannan TLR4 Saccharomyces zymosan TLR2/TLR6 CMV, cytomegalovirus; NOD, nucleotide-binding oligomerization domain; 3P-RNA, 5 0 -triphosphate RNA; RIG, retinoic-acid-inducible protein; TLR, toll-like receptor. kb (NF-kB)) and the TIR domain-containing adaptor protein-inducing-interferon-b- (TRAF-6-,IRF-3-,andNF-kB-) dependent-signaling pathways (Figure 1). 3 Hence, bacterial LPS is a potent inducer of proinflammatory cytokines and type I interferons (IFNs). PG/lipoproteins/lipoteichoic acid TLR1/2 or TLR2/6: TLR2 homo- or heterodimerization at the cell surface allows to detect numerous ligands. TLR2 homodimers recognize PG, a constitutive bacterial cell wall component of all bacteria. 2 TLR1-TLR2 heterodimers recognize triacyl lipopeptides present in the cell wall of Gram-positive bacteria and mycobacteria and TLR2-TLR6 heterodimers recognize diacyl lipopeptides and lipoteichoic acid. 2 The intracellular signaling of TLR1, TLR2, and TLR6 depends on the MyD88- signaling pathway (Figure 1). PG NOD: the cytosolic NLRs detect bacteria that have entered the intracellular cytosol. 2 NOD1 and NOD2 recognize bacterial PG. Diaminopimelic acid, a structural component of PG, ligates NOD1 and muramyldipeptide is a ligand for NOD2. 4 Ligand binding to NOD1 and NOD2 causes their oligomerization and results in NF-kB activation by recruiting receptor-interacting protein/receptor interacting protein-like interacting CLARP kinase, a serine/threonine kinase, to their caspase-recruiting domain by homophilic interactions. NOD1- or NOD2-deficient macrophages fail to produce cytokines in response to bacterial PG. Bacterial cell wall recognition in kidney disease Infections outside the kidney. Extrarenal bacterial infections release bacterial cell wall components into the circulation. For example, LPS exposure triggers systemic cytokine release, renal failure, and eventually fatal septic shock via extrarenal TLR4-MyD88 signaling. 5 TLR4 mutant C3H/HeJ mice do not respond to LPS challenge. Consistent with this observation, patients with loss-of-function mutations in the TLR4 gene are more susceptible to infections with Gram-negative bacteria due to inadequate pathogen control by the innate immune system. 6 Accordingly, patients with defective TLR2 signaling are more susceptible to staphylococcal septic shock. 6 Systemic exposure to TLR2 and TLR4 ligands can also aggravate other types of kidney diseases, for example nephrotoxic serum nephritis, by enhanced production of antibodies and T cells specific for glomerular antigens. 7 Furthermore, bacterial cell wall components elicit intrarenal cytokine release via TLR2 and TLR4 on intrinsic glomerular cells and tubular epithelial cells Podocytes express TLR4 and undergo dedifferentiation after LPS challenge. 8 TLR4 is also expressed at the brush border of proximal tubular epithelial cells. 11 However, the expression and function of most TLRs, RLHs, and NLRs on intrinsic renal cells needs to be better characterized in the future. Interestingly, renal TLR2 is involved in renal ischemia-reperfusion injury suggesting that endogenous ligands to these receptors exist and that these contribute to the pathogenesis of non-infectious types of kidney diseases. 12 Renal infections. In infective pyelonephritis tubular cells and the intrarenal network of myeloid cells both contribute to innate pathogen recognition and host defense. Lack of TLR4 in either cell type impairs host defense against uropathogenic Escherichia coli. 13 By contrast, leptospira is 1052 Kidney International (2007) 72,

3 H-J Anders: Pathogen recognition in the kidney m i n i r e v i e w Intrarenal antigen-presenting cells Intrinsic renal (non-immune) cells Cytoplasm Endosome TLR3 LPS TLR4 TRAM MD2 CD14 TIRAP LP, PG LTA TLR1/2 TLR2/6 Flagellin UPEC TLR5 TLR11 SIGIRR dsrna Mitochondria??? dsdna IPS1 TRIF TRAF3 TBK1 IKKi IRF3 TRAF6 RIP1 IKK NF-κB MyD88 IRAK4 TRAF6 IRF5 TAK1 MAPK AP-1 Endosome ssrnatlr7/8 TLR9 CpG DNA MyD88 RIG-I RICK 3P-RNA NLR MDA5 PG Flagellin dsrna Type 1 interferons Proinflammatory cytokines IRAK4 TRAF6 TRAF3 IRAK1 IKKα IRF7 Type 1 interferons Figure 1 TLRs, RLHs, and NLRs in renal cells. Intrinsic renal non-immune cells express a restricted TLR pattern as compared with intrarenal myeloid dendritic cells (and macrophages). Whether RLHs and NLRs are expressed by both types of renal cells has not yet been characterized in detail. TLRs signal through the MyD88 and/or TIR domain-containing adaptor protein-inducing-interferon-b-signaling pathways for the induction of proinflammatory cytokines and type I IFNs. The RLHs signal through mitochondrial interferon-b promoter stimulator-1 and NLR use receptor-interacting protein-like interacting CLARP kinase. The respective ligands to these receptors are indicated in red (LPS, lipopolysaccharide; PG, peptidoglycan; LTA, lipoteichoic acid; LP, lipoprotein; 3P-RNA, 5 0 -triphosphate RNA). recognized by TLR2. 14 The network of interstitial myeloid dendritic cells and tubular epithelial cells both express TLR1-6 and express chemokines upon exposure to Escherichia coli LPS. 15 Interestingly, the regulation of their TLR signaling is different. Intrarenal dendritic cells, but not tubular epithelial cells, express functional TIR8/single immunoglobulin IL-1 receptor-related molecule, an orphan receptor of interleukin-1 (IL-1)/TLR family with suppressive functions on TLR signalling (Figure 1). However, the significance of defective TLR2 or TLR4 signaling on urinary tract infections in humans is yet poorly evaluated. One may speculate that TLR2 or TLR4 mutations may increase the prevalence of asymptomatic bacteriuria or urosepsis due to a lack of local pathogen control. OTHER BACTERIAL COMPONENTS Flagellin TLR5: the constant D295 and D367 domains of flagellin, an integral component of bacterial flagella, ligates TLR5 on the cell surface and activates antigen-presenting cells to mature and to secrete proinflammatory mediators. 2 Furthermore, TLR5 is expressed at the basolateral membrane of epithelial cells of the gut and lung, for example, facilitating the selective recognition of invasive bacterial growth and ignoring commensal bacteria. TLR5 signaling depends on the MyD88-signaling pathway and involves TRAF-6, IL-1 receptor-associated kinase-4, IRF-5, and NF-kB (Figure 1). 3 Flagellin neuronal apoptosis inhibitory protein 5/ICE protease activating factor: TLR5-independent recognition of flagellin in the cytosol is mediated by members of the NOD- LRR protein family, neuronal apoptosis inhibitory protein 5 and ICE protease activating factor. 2 Uropathogenic Escherichia coli TLR11: TLR11 was found to mediate cytokine release upon exposure to uropathogenic Escherichia coli in a MyD88-dependent manner. TLR11 is expressed in macrophages and in epithelial cells of the kidney and the urinary bladder in mice. Renal TLR11 signaling has a protective role in Escherichia coli pyelonephritis in mice but not in humans as humans lack functional TLR11. 2 Flagellin recognition in kidney disease TLR5 signaling is required for neutrophil recruitment upon inoculation of Escherichia coli into the urinary bladder in mice. 16 Whether this mechanism applies to human urinary tract infection is unknown, but humans require functional TLR5 for defense against Legionella pneumophila. 17 BACTERIAL AND VIRAL DNA DNA serves as a universal pathogen-associated molecular pattern. DNAses rapidly digest extracellular DNA, hence, Kidney International (2007) 72,

4 m i n i r e v i e w H-J Anders: Pathogen recognition in the kidney Table 2 Innate DNA recognition TLR-dependent TLR-independent DNA format CpG-DNA dsdna Self vs. non-self methylation (self)? distinction Cellular compartment endosomes Cytosol Receptor TLR9? Signaling molecules MyD88, TRAF-6, TBK-1, IRF-3 IRAK-1, IRF-7, NF-kB Cell type-specific expression plasmacytoid dendritic cells, B cells, macrophages (mice) Dendritic cells, B cells, fibroblasts, mesangial cells, tubular epithelial cells (all non-immune cells?) MyD88, myeloid differentiation primary-response protein 88; IRAK-1, interleukin-1 receptor-associated kinase-1; IRF-7, interferon regulatory factor-7; NF-kB, nuclear factor-kb; TBK-1, TANK-binding kinase-1; TLR, toll-like receptor; TRAF-6, tumor necrosis factor receptor associated factor. innate DNA receptors do only occur in intracellular endosomes and the cytosol (Table 1). No DNA receptors are known inside the nucleus, which assures tolerance to self- DNA but which may represent a niche for certain DNA viruses. Two DNA formats elicit immunostimulatory effects (Table 2). Cytosin-guanosine (CpG) DNA TLR9: the CpG dinucleotide represents the immunostimulatory motif of bacterial and viral DNA, which ligates TLR9. 2 TLR9 resides in intracellular endosomes of the endoplasmic reticulum, which fuse with endolysosomes for the recognition of bacterial or viral DNA only after phagocytic uptake of the pathogen and after lysis of its wall or envelope structures. Extracellular microbial or self- DNA can escape DNAse digestion and trigger TLR9 signaling when being complexed with other proteins, for example high-mobility group box 1 protein, malarial hemozoin, or immune complexes. 18 TLR9 signaling depends on the MyD88, TRAF-6, IL-1 receptor-associated kinase-1, IRF-7, and NF-kB (Figure 1). 3 Only plasmacytoid dendritic cells and B cells express TLR9. CpG DNA activates plasmacytoid dendritic cells to maturate, to secrete Th1 cytokines for CD8 T-cell priming, and to secrete type 1 IFNs. Furthermore, CpG DNA activates B-cell proliferation and antibody production. dsdna cytosolic DNA receptors: viral dsdna triggers cytokine release when delivered into the cytosol, 2 but the cytosolic DNA receptor(s) are yet unknown. Immune and non-immune cells respond to cytosolic dsdna, which involves the noncanonical IkB kinase TANK-binding kinase-1 and NF-kB-independent activation of mitogenactivated protein kinases (Figure 1). 2 This mechanism allows to recognize DNA viruses that deliver their DNA directly into the cytosol potentially in any cell type and to generate a first tissue-based proinflammatory signal to be further enhanced by professional IFN-producing cells. DNA recognition in kidney disease Infections outside the kidney. Acute or chronic infections with DNA viruses are common, for example, human herpes viruses, Ebstein Barr virus, adenoviruses, or polyomaviruses; and are commonly associated with renal pathology. Experimentally, systemic exposure to CpG DNA has a unique role in triggering the onset of lupus nephritis in autoimmune-prone MRL lpr/lpr but not in MRL wild-type mice. 19 This is because CpG-DNA increases serum cytokine levels, B-cell proliferation, and autoantibody production in these mice. Similar mechanisms operate when a transient exposure to CpG DNA aggravates a preexisting glomerulonephritis. 19 Does TLRindependent cytosolic recognition of dsdna has similar effects? We observed that systemic exposure of complexed double-stranded non-cpg DNA enhances lymphoproliferation, autoantibody production, and glomerulonephritis in nephritic mice (unpublished observation). This may involve local immunostimulatory effects, because the dsdna was found to localize to the cytosol of glomerular and tubular epithelial cells in affected mice after intravenous injection. Renal infections. Cytomegalovirus or polyomavirus commonly cause renal allograft nephropathy in which the viruses replicate in tubular epithelial cells. TLR9 was shown to mediate cytomegalovirus-induced activation of dendritic cells, 20 but MyD88-independent recognition of cytomegalovirus also exists. Cytomegalovirus or polyomavirus do also infect tubular epithelial cells but whether viral DNA can activate innate defense mechanisms in tubular epithelial cells, which lack TLR9 expression remains to be studied. VIRAL RNA The immunostimulatory effects of viral RNA refer to three distinct RNA formats, that is dsrna via TLR3 or via melanoma-differentiation-associated gene (MDA)5 and via RIG-I, U-rich ssrna via TLR7/8, and 5 0 -triphosphate RNA (3P-RNA) via RIG-I (Table 3). 2 Self-RNA is usually ignored by these receptors because (a) RNAses rapidly digest extracellular RNA, (b) self-rna rarely reaches intracellular endosomes, (c) self-rna is mostly methylated, and (d) in self-rna the stimulatory 5 0 -triphosphate motif is capped or modified during post-transcriptional RNA processing. dsrna TLR3: TLR3 recognizes genomic viral dsrna or RNA intermediates generated during viral replication, all of which were shown to trigger antiviral immunity. TLR3 resides in intracellular endosomes that fuse with endolysosomes after phagocytic uptake of viral particles and breakdown of their envelope structures. TLR3 signaling depends on the TIR domain-containing adaptor protein-inducinginterferon-b, TRAF-6, IRF-3, and NF-kB-signaling pathway (Figure 1). 3 The interaction of dsrna with TLR3 is a potent inducer of type I IFNs, the maturation of myeloid dendritic cells and for inducing adaptive T-cell responses. TLR3 is the only nucleic acid-specific TLR, which is expressed in nonimmune cells types like fibroblasts, endothelial cells, mesangial cells, and tubular epithelial cells. 9,10 Viral dsrna cannot activate B cells as they lack TLR3 expression. However, TLR3 is a crucial mediator in the antiviral defense, for example against cytomegalovirus or West Nile virus. 20,21 Self-RNAs were also shown to activate dendritic 1054 Kidney International (2007) 72,

5 H-J Anders: Pathogen recognition in the kidney m i n i r e v i e w Table 3 Innate RNA recognition TLR-dependent TLR-independent RNA format dsrna ssrna dsrna, 3P-RNA Self vs. non-self Methylation (self) Methylation (self) Unmodified 5 -triphosphate motif Cellular compartment Endosomes Endosomes Cytosol Receptors TLR3 TLR7, htlr8 MDA5, RIG-I Signaling molecules TRIF, TRAF-6, TBK-1, IRF-3, NF-kB MyD88, TRAF-6, IRAK1, IRF-7, NF-kB IPS-1, TBK-1, IRF-3, NF-kB Cell types Myeloid DCs, non-immune cells like mesangial cells, endothelial cells plasmacytoid DCs, B cells, macrophages (mice) DCs, B cells, non-immune cells like fibroblasts, mesangial cells, tubular cells DCs, dendritic cells; MyD88, myeloid differentiation primary-response protein 88; IRAK-1, interleukin-1 receptor-associated kinase-1; IRF-7, interferon regulatory factor-7; NF-kB, nuclear factor-kb; 3P-RNA, triphosphate RNA; TBK-1, TANK-binding kinase-1; TLR, toll-like receptor; TRAF-6, tumor necrosis factor receptor associated factor; TRIF, TIR domain-containing adaptor protein-inducing-interferon-b. cells via TLR3, but whether this finding plays a role in vivo is unclear. dsrna MDA5/RIG-I: viral dsrna can still stimulate TLR3-deficient dendritic cells, especially, when transfected directly into the cytosol. 2 The RLHs MDA5 and RIG-I were recently identified to be the cytosolic viral RNA receptors (Table 3). Upon cytosolic transfection viral dsrna induce type-i IFN production and dendritic cell activation via MDA5 and RIG-I, mitochondrial interferon-b promoter stimulator-1, and the noncanonical IkB kinase TANKbinding kinase-1. 2 To date, it remains unclear how cytosolic self-rnas, for example trna, rrna, or mrna, are protected from activating MDA5 and RIG-I. ssrna TLR7/8: genomic viral ssrna or ssrna intermediates ligate TLR7 and htlr8 in intracellular endosomes and trigger antiviral immunity via the MyD88, TRAF-6, IL-1 receptor-associated kinase-1, IRF-7, and NF-kB (Figure 1). 2,3 TLR7 signaling is restricted to plasmacytoid dendritic cells and B cells in humans and activates dendritic cell maturation, to secrete Th1 cytokines for CD8 T cell priming, and to secrete type I IFNs. Type I IFNs amplify TLR7 signaling in an autocrine loop, which fosters proliferation and antibody production in B cells. TLR8 is expressed in human monocytes and can enhance the production of proinflammatory cytokines, especially, IL-12. These effects integrate to a potent antiviral immune response, which can be mimicked for therapeutic use. The TLR7 agonist imiquimod (5% cream) is used to treat external genital warts, basal cell carcinoma, and actinic keratosis, and is in clinical trials against human papillomavirus. 22 Self-RNA may eventually trigger TLR7 signaling when RNA-containing immune complexes are internalized via the B-cell receptor into intracellular endosomes of B cells or via Fc receptors into dendritic cells and macrophages. 18 For example, lupus immune complexes containing U1 small nuclear ribonuclear protein RNA specifically ligate TLR7 in plasmacytoid dendritic cells. 18 The importance of TLR7 in the pathogenesis of lupus nephritis was recently documented by studies with lupus-prone TLR7-deficient MRL lpr/lpr mice, TLR7-overexpressing mice, 18 and in nephritic MRL lpr/lpr mice treated with a TLR7 antagonist triphosphate RNA RIG-1: RIG-I is a cytosolic receptor for viral 5 0 -triphosphate RNA, a characteristic of many viral ssrnas (Table 3). 24 RIG-I and MDA5 share the same signaling pathway (Figure 1). 3 The cell type-specific expression of RIG-I is less clear but TLR-independent recognition of ssrna is a feature of many immune and non-immune cell types including mesangial cells. RNA recognition in kidney disease Infections outside the kidney. RNA virus infections, like with hepatitis C virus, release viral RNA protein complexes into the circulation, which reach or precipitate in the glomerular mesangium, a condition often associated with glomerulonephritis. TLR3 mrna is specifically induced in hepatitis C glomerulonephritis but not in non-hcv glomerulonephritis. 25 In fact, viral dsrna localizes to intracellular endosomes of mesangial cells after injection fostering local production of IL-1, IL-6, IL-8, monocyte chemotactic protein-1/ccl2, regulated on activation, normally T-cell expressed and secreted/ccl5. 19,25 Furthermore, the antiproliferative and proapoptotic effect of viral dsrna on cultured mesangial cells is consistent with mesangiolytic lesions of nephritic mice repeatedly challenged with viral dsrna injections. 19 In mesangial cells, cytokines like IFN-g and tumor necrosis factor upregulate TLR3 and enhance TLR3 signaling. 10,25 The cell type-specific expression of TLR3 and TLR7/8 determine the different TLR-mediated biological effects of viral dsrna and ssrna. In contrast to TLR3, TLR7 is absent on nonimmune cells but present on B cells. Hence, systemic exposure to TLR7 agonists triggers antibody production and glomerular immune complex deposits in immune complex glomerulonephritis but lacks the activation of intrinsic renal cells. 19 However, both TLRs can activate intrarenal immune cells such as macrophage infiltrates present in glomerulonephritis. TLR3 and TLR7 co-activation can have synergistic effects on the activation of dendritic cells but not on B cells or renal cells, which do not express both receptors. Hence, TLR3 and TLR7 co-activation had no additive effects on experimental glomerulonephritis. 26 Furthermore, viral dsrna and ssrna are unable to trigger the onset of de novo glomerulonephritis. Not much is yet known about the functional significance of TLR-independent viral RNA recognition in the kidney. Immunostaining colocalized RIG-I protein to the mesangial area of patients with active lupus nephritis and the staining Kidney International (2007) 72,

6 m i n i r e v i e w H-J Anders: Pathogen recognition in the kidney intensity correlated with disease activity. 27 Cultured glomerular endothelial cells, mesangial cells, and tubular epithelial cells express basal levels of RIG-I and MDA5 and both are induced upon exposure to proinflammatory cytokines. Whether exposure to viral 5 0 -triphosphate RNA modulates lupus nephritis, and if so, via which immune mechanisms remains to be examined. Renal infections. Few RNA viruses cause renal pathology by replicating in renal cells. Human-immunodeficiency virus although shown to replicate in glomerular cells, but these cells lack TLR7. 19,25 Whether human-immunodeficiency virus RNA ligates the cytosolic RNA receptors is unknown to date. However, the diverse clinical pattern of humanimmunodeficiency virus nephropathy may include multiple other pathomechanisms. Acute renal failure in Hantanvirus infection is associated with a septic shock-like massive increase in renovascular permeability, proteinuria, and intrarenal cytokine expression. Whether this involves viral recognition via TLR2-4 or the cytosolic RNA receptors in vascular endothelial cells, podocytes, and tubular epithelial cells remains to be studied. By contrast, DNA viruses like cytomegalovirus are known to generate RNA transcripts activate dendritic cells via TLR3. 20 However, the functional role of intrarenal viral RNA recognition for renal pathology remains to be studied. Summary and outlook The evolving data on innate pathogen recognition receptors provide novel concepts about how infections can trigger renal pathology. TLRs, RLHs, and NLRs all activate immune cells upon recognition of infective organisms. Extrarenal pathogen recognition can cause renal pathology by systemic cytokine release or by immune complex formation. Furthermore, circulating microbial components can activate immune and non-immune cells in the kidney. Renal non-immune cells express a restricted pattern of TLRs but the expression patterns of NLRs and RLHs has not been characterized in detail. TLRs on, for example, tubular epithelial cells also mediate innate immune signaling during renal infection, but whether the intrarenal network of dendritic cells contributes to pathogen recognition via these receptors has not been formally demonstrated. The specificity of a few innate recognition receptors for universal pathogen-associated molecules is not absolute and they definitely recognize and trigger danger signals in response to self-molecules. To elucidate the roles of these receptors for the pathogenesis of non-infectious kidney diseases and renal infections appears to be as a promising field for unexpected discoveries in the future. ACKNOWLEDGMENTS This work was supported by grants from the Deutsche Forschungsgemeinschaft (AN372/9-1, AN372/8-1, GRK 1202), the Fritz Thyssen Foundation, and the EU Integrated Project INNOCHEM (FP ). Unfortunately, owing to the limited number of references allowed in the mini review format important research contributions could not be included into the reference list. I thank A Ramanjaneyulu for critically reading this paper. REFERENCES 1. Creagh EM, O Neill LA. TLRs NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol 2006; 27: Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124: Kawai T, Akira S. TLR signaling. Semin Immunol 2007; 19: Fritz JH, Ferrero RL, Philpott DJ, Girardin SE. NOD-like proteins in immunity, inflammation and disease. Nat Immunol 2006; 7: Cunningham PN, Wang Y, Guo R et al. Role of Toll-like receptor 4 in endotoxin-induced acute renal failure. 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