Tracking the Toll of Kidney Disease
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BRIEF REVIEW www.jasn.org
Tracking the Toll of Kidney Disease
Anushree C. Shirali* and Daniel R. Goldstein†
Divisions of *Nephrology and †Cardiology, Department of Internal Medicine, Yale University School of Medicine, New
Haven, Connecticut
ABSTRACT
Since the discovery of the Toll-like receptors and their crucial role as modulators of sponse to viral infection, express TLR7
innate immunity, there has been increasing appreciation of their role in human and 9 but not other TLR.6 In the kidney,
health and disease. Toll-like receptor signaling is critical in defending against tubular epithelial cells and mesangial
invading microorganisms, but sustained receptor activation is also implicated in the cells express TLR 1 through 4 and 6.7,8
pathogenesis of inflammatory diseases. Here we review the role of Toll-like recep- Data on TLR expression in podocytes
tors and their endogenous ligands in various renal diseases, particularly their and other glomerular components are
activation in the inflammatory response of ischemic kidney injury, organ transplan- sparse, although a recent study found
tation, and immune-mediated glomerulonephritis. constitutive TLR2 staining in glomerular
capillary endothelial cells.9 Most TLR re-
J Am Soc Nephrol 19: 1444 –1450, 2008. doi: 10.1681/ASN.2008010123
side on the cell surface, except TLR 3 and
7 through 9, which are found intracellu-
larly to encounter ligands in endosomes
The Toll-like receptors (TLR) were dis- TLR: STRUCTURE, EXPRESSION, or lysosomes.3 Thus, by achieving wide
covered more than a decade ago as senti- AND SIGNALING PATHWAYS distribution in different tissues, cells, and
nel receptors for the mammalian innate subcellular compartments, TLR are ex-
immune system.1 TLR are among a TLR are mammalian homologues of the ceptionally well-positioned sentinels
growing number of receptors that recog- Toll receptor, first described in Drosoph- against invading pathogens.
nize pathogen-associated molecular pat- ila as playing a critical role in embryo- The cytosolic domains of TLR recruit
terns as infectious non-self ligands and, genesis and antifungal immunity.1 At adaptor proteins and initiate signaling
in response, ignite an inflammatory cas- present, 11 human and 13 mouse TLR pathways in response to ligand binding
cade that includes activation and matu- have been identified,3 and all are struc- (Figure 1). Five adaptor proteins have
ration of dendritic cells (DC), the most turally similar to the Toll receptor, high- been discovered: Myeloid differentiation
potent antigen-presenting cells of innate lighting in terms of evolution that this is factor 88 (MyD88), MyD88 adaptor–like
immunity.2 TLR-activated DC induce an ancient system for immune protec- (MAL; also known as TIRAP), TIR-do-
naive T lymphocytes to mature into an- tion. TLR are type I integral membrane main-containing adaptor protein–in-
tigen-specific effector T cells, particu- glycoproteins. They contain a cytoplas- ducing IFN- (TRIF; also known as TI-
larly of the Th1 lineage.2 Thus, TLR mic domain named the Toll/IL-1R (TIR) CAM1), TRIF-related adaptor molecule
link innate and adaptive immune re- domain because of sequence homology (TRAM; also known as TICAM2), and
sponses, both of which are critical to with the IL-1 receptor (IL-1R).4 The ex- sterile ␣- and armadillo motif– contain-
host defense against pathogens. TLR tracellular portion of TLR contains ing protein.10 All TLR use the MyD88
are also implicated in the pathogenesis unique tandem areas of leucine-rich re- pathway, except TLR3, which signals
of several inflammatory diseases, in- peats in contrast to the Ig-like regions
cluding kidney diseases. In particular, found in the IL-1R.4
increasing evidence suggests that endog- TLR are found on a variety of cell Published online ahead of print. Publication date
available at www.jasn.org.
enous ligands activate TLR, resulting in types, including epithelial cells, endothe-
the antigen-independent inflammation lia, DC, monocytes/macrophages, and B Correspondence: Dr. Daniel R. Goldstein, 333 Ce-
dar Street, 3 FMP, P.O. Box 208017, New Haven, CT
that accompanies ischemic acute kidney and T cells.5 One particular cell type may 06520-8018. Phone: 203-785-3271; Fax: 203-785-
injury (AKI), solid organ transplant re- express only a limited number of TLR.5 7567; E-mail: daniel.goldstein@yale.edu
jection, and immune-mediated glomer- For example, plasmacytoid DC, special- Copyright 䊚 2008 by the American Society of
ulonephritis. ized DC that secrete type I IFN in re- Nephrology
1444 ISSN : 1046-6673/1908-1444 J Am Soc Nephrol 19: 1444–1450, 2008www.jasn.org BRIEF REVIEW
Flagellin el.15 As demonstrated by Cunningham et
LPS al.,15 this is a systemic effect. Kidneys
Lipopeptide
TLR5
from wild-type mice transplanted into
TLR4⫺/⫺ recipients resisted LPS-in-
TLR6 TLR4
TLR2
MyD88 TIRAP TRAM
TLR1
TIRAP MyD88 TRIF duced AKI, whereas TLR4⫺/⫺ kidneys
MyD88
transplanted into wild-type recipients
sustained severe AKI triggered by LPS.
TLR7/8 TLR3
NF-kΒ TRIF The identity of TLR agonists has
MyD88
dsRNA
ssRNA grown to include endogenous ligands
dsDNA TLR9 IRF5/7 IRF3
(Table 1) such as heat-shock proteins
(e.g. CpG) ENDOSOME (HSP), high mobility box group 1
ENDOSOME NUCLEUS
(HMGB1) nuclear protein, and hyaluro-
nan (HA).5,12,13 Although there is con-
CYTOPLASM
IFN-α/IFN-β, Inflammatory IFN-β, IFN
cern that microbial contamination may
IFN inducible cytokines, inducible be a confounding factor,16 the weight of
genes chemokines genes
experimental evidence supports that
Figure 1. TLR and their major signal adaptors. these molecules activate TLR. Although
this presents a paradigm shift in the tra-
through TRIF. TLR2 and TLR4 recruit sponses, all of which support a robust in- ditional concept of immune surveillance
MyD88 through MAL/TIRAP, whereas nate immune response and subsequently as self/non-self discrimination (the
TLR4 also engages TRIF through shape adaptive immunity. “stranger” hypothesis), it more readily
TRAM.10 Once stimulated, the MyD88- explains a role for the innate immune
dependent pathway leads to activation of system in AKI, organ transplantation,
the NF-B, mitogen-activated protein TLR: LIGANDS SIGNAL and autoimmune disease, as Matzinger17
kinase, and IFN regulatory factor path- “STRANGER” AND “DANGER” proposed in the “danger” model. Con-
ways of inflammation, cell growth, and cerning AKI and organ transplantation,
differentiation.10 The TRIF-dependent TLR respond to a variety of activators these models support the idea that anti-
pathway also activates NF-B with de- (Table 1), including DNA, RNA, lipids, gen-independent injury, such as isch-
layed kinetics and additionally induces and peptide products from bacteria, vi- emia reperfusion or vessel attachment of
IFN regulatory factor 3, a transcription ruses, fungi, and synthetically derived ischemic allografts, initiates a common
factor necessary for production of type I compounds.5,12,13 Among the best char- pathway of innate immune activation
IFN.11 TLR 1, 2, and 6 contain a phos- acterized ligands, LPS is the cell wall and inflammation.
phatidylinositol 3-kinase (PI3K) binding component of Gram-negative bacteria
motif11 and activate NF-B through that plays a prominent role in the patho-
PI3K independent of MyD88. Thus, de- genesis of sepsis.14 LPS activates TLR4, ENDOGENOUS LIGANDS IN
pending on the specific combinations of and this interaction contributes to the ISCHEMIA REPERFUSION INJURY
TLR ligand, cell type, receptor, and adap- inflammation that characterizes LPS-in-
tor protein, different signaling cascades duced AKI, as defined by elevated blood Ischemia reperfusion injury is a complex
result in a diverse range of cellular re- urea nitrogen (BUN) in a murine mod- pathophysiologic process that occurs
Table 1. TLR and a representative list of known exogenous and endogenous TLR agonists5,12,13
Ligand
TLR
Exogenous Endogenous
TLR1 ⫹ TLR2 Triacyl lipopeptides, lipoarabinomannan
TLR2 Peptidoglycan, zymosan HSP 70, HMGB1, HA
TLR2 ⫹ TLR6 Diacyl lipopeptides, lipoteichoic acid
TLR3 dsRNA, siRNA mRNA
TLR4 LPS, peptidoglycan, taxol Tamm-Horsfall glycoprotein, HA, HMGB1, heparan sulfate, fibronectin
domain A, surfactant protein A, modified LDL
TLR5 Flagellin
TLR7 ssRNA, imiquimod RNA
TLR8 ssRNA
TLR9 CpG DNA (dsDNA) Chromatin complex
TLR10 Unknown
TLR11 Profilin-like molecule
J Am Soc Nephrol 19: 1444 –1450, 2008 TLR and Kidney Disease 1445BRIEF REVIEW www.jasn.org
when blood flow is restored to ischemic HMGB1 is another endogenous mol- of Bowman’s capsule. During unilateral
tissues. It occurs with profound hypovo- ecule increasingly implicated in ischemia ischemia, expression of both TLR rapidly
lemia, sepsis, and transplantation of vas- reperfusion injury. HMGB1 is a highly increased in ischemic kidneys, up to
cularized allografts. Ischemia reperfu- conserved nuclear protein that binds four- to five-fold over basal levels at 5 d
sion injury leads to poor clinical DNA and facilitates interactions between after ischemia, especially in distal tubular
outcomes, for example, the association DNA and nuclear proteins, which regu- epithelia.30 Leemans et al.31 explored the
of delayed graft function and allograft re- late transcription.26 It is released during functional significance of these findings
jection with prolonged cold ischemia cell necrosis and binds to the receptor for by comparing bilateral kidney ischemia
time. Renal ischemia reperfusion injury advanced glycation end products, TLR2, reperfusion injury in TLR2 null mice ver-
is associated with an influx of neutro- and TLR4. In addition, HMGB1 is re- sus wild-type mice and found that isch-
phils, macrophages, and T cells, which leased during late phases of LPS-induced emia-induced renal dysfunction, as as-
cause inflammation and lead to chronic septic shock in mice and is present in pa- sessed by BUN/Cr and histologic
renal dysfunction.18 Various endoge- tients with sepsis.27 Moreover, adminis- evidence of acute tubular necrosis, was
nous ligands are implicated as mediators tration of anti-HMGB1 antibodies pro- TLR2 dependent. Experiments with
of this process.16,19 Table 1 lists several of tects against lethality from established bone marrow chimeras demonstrates
these substances, including two exten- endotoxemia.26 Recent studies found that TLR2 expression in renal paren-
sively studied ligands: HA and HMGB1. that HMGB1 plays a central role in me- chyma mediates inflammation in this ex-
HA is a glycosaminoglycan compo- diating the inflammatory response to perimental model.31
nent of the extracellular matrix and is ischemia reperfusion injury, particularly Within the past year, the role of other
abundantly present in the renal me- in models of liver ischemia. The Billiar TLR as well as TLR adaptor proteins has
dulla.20 HA is the major ligand for CD44, laboratory demonstrated the expression been investigated during renal ischemia.
a transmembrane glycoprotein receptor, of HMGB1 increases in murine livers One study found that bilateral renal isch-
but studies suggest HA also transduces soon after ischemia reperfusion injury emia reperfusion injury in TLR2⫺/⫺
inflammatory signals through TLR2 and remains elevated up to 24 h.28 In mice resulted in less renal impairment
alone or in synergy with TLR4.21 A recent vitro studies with cultured hepatocytes than in wild-type mice but through
review21 discussed HA in depth, including found hypoxia was sufficient to stimulate MyD88-independent mechanisms.9 This
its role as an innate immune activator. HMGB1 upregulation.28 Use of a neu- suggests involvement of MyD88-inde-
Studies of murine models reported tralizing antibody against HMGB1 after pendent pathways for TLR2 signaling ac-
increased renal expression of HA as ischemia reperfusion injury decreased tivated by kidney ischemia reperfusion
well as the HA receptor, CD44, after local TNF-␣ and IL-6 production and af- injury, through either PI3K or TIRAP.
kidney ischemia reperfusion injury.22,23 forded protection of liver function, as Wu et al.29 suggested that TLR4 also par-
HA-CD44 interactions are critical for in- shown by decreased serum alanine ami- ticipates in ischemia-induced inflamma-
flammation induced by renal ischemia. notransferase levels.28 HMGB1 uses TLR tion. In an in vivo model of renal isch-
Rouschop et al.24 demonstrated that 24 h signaling in mediating hepatic ischemia emia reperfusion injury, the authors
after bilateral kidney ischemia reperfu- reperfusion injury; TLR4 knockout mice demonstrated that TLR4⫺/⫺ mice had
sion injury, CD44⫺/⫺ mice had better re- were resistant to the effects of the anti- lower creatinine levels, less histologic ev-
nal function, as measured by BUN and HMGB1 antibody. Whether HMGB1 is idence of tubular injury, and decreased
creatinine (BUN/Cr) levels, and less his- an endogenous ligand activating innate neutrophil influx compared with wild-
tologic evidence of tubular necrosis immune signaling during kidney isch- type controls at several time points after
and brush border loss compared with emia reperfusion injury is unclear, al- renal ischemia.29 Studies with bone mar-
wild-type mice. Renal inflammation was though a recent study reported increased row chimeric mice confirmed that TLR4
also abrogated without CD44, because renal HMGB1 expression after kidney signaling on renal parenchyma is neces-
CD44⫺/⫺ mice had decreased infiltra- ischemia.29 sary for the complete pathologic profile
tion of neutrophils compared with wild- of ischemia reperfusion injury.29 In con-
type mice. This effect is independent of trast to the previous study,9 MyD88⫺/⫺
cytokine and chemokine levels. Interest- TLR SIGNALING IN AKI mice in this model of ischemia reperfu-
ingly, although mutant mice displayed sion injury have a similar phenotype
decreased inflammation, they also dis- Several reports in the past few years pro- of renal function and tubular injury as
played a slower tempo of neutrophil posed a role for TLR signaling in isch- TLR4⫺/⫺ mice.29 Furthermore, renal ex-
clearance compared with wild-type emic kidney injury. Using in situ hybrid- pression of several endogenous ligands
mice.24 Perhaps CD44 plays a role in ization, Wolfs et al.30 found that TLR2 increases after ischemia reperfusion in-
clearing renal inflammation in later and TLR4 are constitutively expressed in jury, including biglycan, HMGB1, and
stages of ischemia reperfusion injury, as healthy, wild-type murine kidneys, pri- HA, but not HSP 70,29 but there were no
had been demonstrated in an experiment marily in proximal and distal tubule ep- mechanistic data linking the release of
model of acute lung injury.25 ithelial cells (TEC) and in the epithelium these ligands to the altered phenotype
1446 Journal of the American Society of Nephrology J Am Soc Nephrol 19: 1444 –1450, 2008www.jasn.org BRIEF REVIEW
seen without TLR4. Clearly, this is an models without MyD88 signaling.40 9, which recognize nucleic acids (Table
area that merits further investigation. TLR-dependent MyD88 signaling im- 1), in mediating the inflammatory re-
pairs the induction of transplantation sponse in autoimmune disease. Mar-
tolerance.41 In this work, MyD88 signal- shak-Rothstein’s46,47 seminal work in
INNATE IMMUNE ACTIVATION IN ing activates inflammatory responses by murine models of systemic autoimmune
ORGAN TRANSPLANTATION DC during transplantation, which subse- disease established in vitro that self-
quently primes alloreactive T cells.41 IgG2a antibodies complex with chroma-
Experimental and clinical evidence sug- These primed T cells are resistant to the tin or RNA autoantigens to stimulate B
gests an association between endogenous immunoregulatory properties of regula- cell proliferation and autoantibody for-
ligands and allograft rejection.20,32,33 We tory T cells. Similar findings have been mation through sequential engagement
previously hypothesized that antigen-in- found in other studies.42,43 In summary, of the B cell receptor and TLR9 or TLR7,
dependent ischemia reperfusion injury multiple innate immune pathways— respectively; however, Patole et al.48
after organ implantation would release TLR dependent/MyD88 independent found that in vitro binding of synthetic
innate immune ligands, and this would and/or non-TLR pathways—are neces- dsRNA to TLR3 failed to activate B cells
initiate TLR signaling on either host or sary for acute allograft rejection; how- and produce anti-DNA antibodies. To
recipient DC, leading to DC maturation ever, MyD88 signaling inhibits the in- clarify the role of TLR in autoimmunity,
and priming of alloimmune responses. duction of transplantation tolerance. subsequent studies have investigated the
In testing this hypothesis in a murine mi- We also investigated the role of en- in vivo importance of TLR for autoim-
nor mismatch (H-Y) skin allograft dogenous ligands in organ transplanta- mune disease.
model, we found that acute allograft re- tion. There is no increase in levels of HSP Christensen et al.49,50 backcrossed
jection depended on MyD88 signaling.34 70 in fully mismatched skin grafts under- Fas-deficient MRL/Mplpr/lpr (MRL/lpr)
Specifically, MyD88⫺/⫺ females were going acute rejection44; however, in the mice, an accepted murine model of ge-
unable to reject skin grafts from H-Y–incompatible murine skin graft netic susceptibility to SLE characterized
MyD88⫺/⫺ males, whereas rejection was model, HA levels were increased during by spontaneous development of an SLE-
preserved in wild-type controls.34 In ad- acute rejection.45 We also found in- like syndrome and immune complex glo-
dition, MyD88⫺/⫺ mice displayed re- creased levels of HA in the bronchial la- merulonephritis, to TLR3⫺/⫺, TLR7⫺/⫺,
duced numbers of mature DC in drain- vage fluid of lung transplant recipients and TLR9⫺/⫺ mice. They found that TLR9
ing lymph nodes after transplantation, with clinical evidence of rejection com- but not TLR3 is required for DNA or chro-
suggesting the defective alloimmune re- pared with patients who remained free of matin autoantibody production.49,50 In the
sponse in MyD88⫺/⫺ mice occurs in the rejection.45 In vitro studies showed that absence of TLR9, MRL/lpr mice shift their
initiation phase of the immune response stimulation of DC with proinflamma- autoantibody repertoire, with nuclear
to transplantation.34 Lack of MyD88 sig- tory low molecular weight HA fragments staining patterns suggestive of increased
naling also leads to defective CD8 alloim- leads to DC maturation, including up- anti-RNA antibodies.50 In contrast,
mune priming and Th1 alloimmune re- regulation of co-stimulatory molecules MRL/lpr mice crossed to a TLR7⫺/⫺
sponses.34 The identity of the upstream CD40, CD86, and CCR7 and production background lack antibodies directed
TLR that initiate MyD88 signaling is not of TNF-␣.45 Interestingly, although HA- against RNA autoantigens but have in-
clear, although we did find that TLR2⫺/⫺ induced TNF-␣ production is MyD88 tact anti-DNA antibodies.50 Despite the
mice have a delayed tempo of graft rejec- dependent, upregulation of co-stimula- antibody profiles, clinical disease activ-
tion,34 whereas, in agreement with other tory molecules is MyD88 independent ity diverges with TLR7 versus TLR9 defi-
reports of a skin allograft model,35 TLR4 and depends on TIRAP signaling.45 The ciency. Lupus-prone, TLR7-deficient
did not play a significant role. Perhaps in vivo importance of TIRAP signaling to mice display fewer skin lesions and have
multiple TLR act in concert to deliver the transplantation is unclear. modestly less renal disease, as defined by
immune response in clinical organ trans- a composite score of glomerular lesions
plantation. Alternatively, LPS contami- and interstitial infiltrates, than TLR7-
nation during organ transplantation in TLR INVOLVEMENT IN sufficient control MRL/lpr mice.50 In
humans may be a confounding factor.36 AUTOIMMUNE contrast, TLR9 deficiency increases dis-
Indeed, clinical studies of renal37,38 or GLOMERULONEPHRITIS ease activity in MRL/lpr mice, with mice
lung transplant recipients39 with hypore- displaying more severe skin lesions and
sponsive TLR4 polymorphisms have de- Many of the autoantibodies used clini- greater scoring for glomerular and inter-
creased acute allograft rejection rates. cally as markers of autoimmune disease stitial renal lesions compared with wild-
In subsequent studies, we determined activity, particularly in systemic lupus er- type littermates. These findings correlate
that MyD88 signaling is not critical for ythematosus (SLE), target nucleic acids with distinct differences in immune ac-
rejection of fully allogeneic skin or car- and their associated substructures. This tivity,50 because immune cells from
diac allografts, although Th1 alloim- clinical observation supports an involve- MRL/lpr TLR7⫺/⫺ mice, including T
mune responses are decreased in these ment for TLR, particularly TLR 3, 7, and cells, B cells, and plasmacytoid DC have
J Am Soc Nephrol 19: 1444 –1450, 2008 TLR and Kidney Disease 1447BRIEF REVIEW www.jasn.org
an immature phenotype, whereas the tion of IFN-␣ and other proinflamma- ulonephritis in susceptible individu-
same cells in MRL/lpr TLR9⫺/⫺ mice, tory cytokines in human plasmacytoid als.62 Because TLR mediate immune
particularly plasmacytoid DC, have an DC activated by TLR9 agonists. Tian et responses against both infection and in-
activated phenotype. Taken together, al.58 found opposite results in a similar jury, they may prove useful targets in
these results suggest in experimental SLE study in mice with purified HMGB1 modulating immune activation in sev-
that TLR7 promotes whereas TLR9 complexing with CpG oligonucleotides eral models of glomerulonephritis.
dampens inflammation in target organs, and stimulating enhanced inflammatory
including the kidney. In partial agree- cytokine production through TLR9-
ment with this finding, Pawar et al.51 MyD88 and receptor for advanced gly- CONCLUSIONS
found that inhibitory synthetic oligode- cation end products– dependent path-
oxynucleotides with immunoregulatory ways. Experimental and clinical evidence sup-
sequences specific for TLR7 decrease in- Although these studies showed con- ports the involvement of TLR in devel-
terstitial and glomerular injury in MRL/ trasting results, both studies suggested opment of kidney diseases, including
lpr mice. Dual inhibition of TLR7 and that cross-talk between endogenous li- AKI, transplant rejection, and autoim-
TLR9 by a different immunoregulatory gands modulates TLR9 responses. TLR mune glomerulonephritis. Although
sequence do not have an additive reno- function in such an interlinked system to these pathologic states are diverse, they
protective role but do not abrogate the maintain tissue homeostasis after injury share a common pathway of TLR activa-
protection afforded by lone TLR7 block- by allowing effector mechanisms of in- tion that begins with tissue injury. In this
ade, either. flammation and repair while avoiding model (Figure 2), various forms of renal
The increased numbers of activated loss of self-tolerance to neoantigens cre- injury, including ischemia reperfusion
plasmacytoid DC in TLR9⫺/⫺ MLR/lpr ated by the same mechanisms. Under- injury and immune complex deposition,
mice partly explain the results by Chris- standing the pathways that govern these induce the release of endogenous ligands
tensen et al.50 Plasmacytoid DC secrete systems is critical in determining safe and to activate TLR. As a result, an adaptive
type I IFN in response to immune com- effective therapeutics for lupus and lu- immune response is primed, culminat-
plexes containing either RNA or DNA, pus-associated kidney disease. ing in robust effector cell responses that
although IFN-␣ responses to RNA are Several laboratories point to the impor- cause renal inflammation. With con-
more robust.6,52 Indeed, TLR9⫺/⫺ mice tance of TLR signaling in models of glo- trolled inflammatory signals, the kidney
have higher serum levels of IFN-␣ com- merulonephritis besides lupus nephritis. In undergoes repair and recovers function;
pared with wild-type controls.50 Clini- particular, Brown et al. found that both ac- however, with unresolved inflammation,
cally, higher levels of type 1 IFN correlate tivation of TLR259,60 and TLR461 in a mu- TLR activation persists, resulting in a cy-
with progression and severity of disease, rine model of crescentic glomerulonephri- cle of chronic renal injury, inflamma-
including renal manifestations.53 Per- tis induced by an anti-mouse glomerular tion, and dysfunction. Further studies
haps the shift in RNA-specific antibodies basement membrane antibody exacer- are needed to determine how the im-
in TLR9⫺/⫺ animals induces stronger bated the severity of nephritis. These mune system modulates TLR activation
type I IFN responses and more severe studies are particularly interesting be- to maintain the balance between tissue
disease. Clearly, downstream effects of cause of the known clinical association repair and injury. Such lines of investiga-
TLR signaling in immune cell subsets between infection and subsequent de- tions may lead to novel therapeutics for
and their specific effects on renal pathol- velopment or exacerbation of glomer- kidney diseases.
ogy in lupus are potential areas of inves-
tigation.
The studies by Christensen et al.50 ACUTE KIDNEY INJURY Release of
TLR
contrast with earlier in vitro52 and in Ischemia, Ischemia endogenous
ligands activation
reperfusion,
vivo54,55 studies supporting an immuno- nephrotoxic ?
toxin-induced
necrosis
stimulatory role of TLR9 agonists in
Organ Ischemia Renal Priming of adaptive
MRL/lpr mice. The in vivo findings by transplantation reperfusion injury immune response
Christensen et al.,50 confirmed by other Immune
complex
reports,56 clearly indicate TLR9 interac- Systemic deposition
autoimmune Renal
tions are more complex than previously disease Infections,
other triggers? inflammation
thought. Emerging data suggest TLR9 Sustained
S t i d Dampened
inflammatory triggers/ inflammatory triggers/
activation on plasmacytoid DC by nu- defective clearance clearance of
cleic acids and subsequent IFN-␣ pro- of inflammation inflammation
Acute rejection Graft dysfunction CKD Repair and
duction is regulated by endogenous li- AKI Renal fibrosis CKD recovery
gands other than nucleic acids.
Popovic et al.57 found that recombi- Figure 2. Role of TLR in the cycle of renal injury induced by ischemia, organ transplan-
nant HMGB1 inhibits in vitro produc- tation, or autoimmunity. AKI, active kidney disease; CKD, chronic kidney disease.
1448 Journal of the American Society of Nephrology J Am Soc Nephrol 19: 1444 –1450, 2008www.jasn.org BRIEF REVIEW
ACKNOWLEDGMENTS G, Marshak-Rothstein A: Toll-like receptors, liver ischemia-reperfusion. J Exp Med 201:
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D.R.G. is supported by National Institutes of 2005 P, Eris JM, Alexander SI, Sharland AF, Chad-
Health grant AI064660 and by the Roche Or- 14. Cohen J: The immunopathogenesis of sep- ban SJ: TLR4 activation mediates kidney
gan Transplantation Research Foundation. sis. Nature 420: 885– 891, 2002 ischemia/reperfusion injury. J Clin Invest
A.C.S. is supported by National Institutes of 15. Cunningham PN, Wang Y, Guo R, He G, 117: 2847–2859, 2007
Quigg RJ: Role of toll-like receptor 4 in en- 30. Wolfs TG, Buurman WA, van Schadewijk A,
Health grant T32 5T32DK 007276-30.
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16. Wallin RPA, Lundqvist A, Moré SH, von Bo- tor 2 and 4 by renal epithelial cells: IFN-
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DISCLOSURES
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