NDT Advance Access originally published online on June 7, 2005
Nephrology Dialysis Transplantation 2005 20(8):1529-1532; doi:10.1093/ndt/gfh922
© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Editorial Comment
Toll-like receptors recognize uropathogenic Escherichia coli and trigger inflammation in the urinary tract
Hans-Joachim Anders and
Prashant S. Patole
Nephrological Center, Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany
Correspondence and offprint requests to: Dr H.-J. Anders, Medizinische Poliklinik der LMU, Pettenkoferstr. 8a, D-80336 Munich, Germany. Email: hjanders{at}med.uni-muenchen.de
Keywords: chemokines; immunity; infection; leukocytes
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Introduction
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Urinary tract infection (UTI) is one of the most common types
of infection. In the USA, >US$1.6 billion per year are spent
in the management of UTI [
1]. Amongst the pathogens that can
cause UTI, uropathogenic
Escherichia coli (UPEC) has been found
to be the causative organism in
80% of cases. A number of pathogen-related
virulence factors have been identified that relate mostly to
pathogen adhesion to the epithelial lining of the urinary tract
[
2–4]. In addition, patient-related factors determine
the prevalence and severity of UTI. Diabetes, immunosuppression,
reflux and obstruction due to structural abnormalities of the
urinary tract or pregnancy are known to predispose to UTI. These
conditions affect either physiological urine flow or cellular
immunity against uropathogenic agents. However, the patient-related
risk for UTI may also be determined by pathogen recognition
and pathogen-induced signalling for host defence. Host defence
in UTI is based on innate immunity. Thus, which receptors recognize
uropathogenic pathogens, and what are the subsequent signalling
cascades that concert antibacterial immunity? The recent discovery
of the Toll-like receptor (TLR) family has identified a group
of such receptors that appear to have important functions not
only for pathogen recognition but also for innate immune activation
[
5]. In this article, we present the current view on TLRs in
UTI. Based on these data, we propose a working hypothesis and
raise new questions that deserve further study in this field.
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Toll-like receptors are innate pathogen recognition receptors
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Innate immune recognition is based on so-called pattern recognition
receptors (PRRs). Important families of PRRs include scavenger
receptors, complement receptors and mannose receptors. PRRs
recognize pathogen-associated molecular patterns (PAMPs). Several
PRRs can recognize the same pathogen through different PAMPs.
Contrarily, various classes of pathogens can be recognized by
the same PRR. Recently, a new family of PRRs was discovered,
the TLRs [
6]. The TLR family consists of 12 members, but ligands
and functions for TLR10 and TLR12 have not yet been identified
(
Figure 1). A subgroup of the TLRs, namely TLR3, TLR7, TLR8
and TLR9, recognize various types of nucleic acids. Nucleic
acid-specific TLRs are mostly localized in intracellular endosomes,
allowing the recognition of complexed nucleic acids that are
delivered to that compartment [
7]. TLR1 and TLR6 are localized
on the cell surface and activate different signalling pathways
upon heterodimerization with TLR2 [
8]. TLR1/TLR2 and TLR6/TLR2
heterodimers recognize various forms of lipopeptides that occur
on both Gram-positive and Gram-negative bacteria [
9]. TLR5 recognizes
flagellin, and its localization at basolateral membranes of
enterocytes allows selective recognition of enteroinvasive forms
of flagellated pathogens in the intestinal tract [
10]. Finally,
TLR4 is a critical component of the lipopolysaccharide (LPS)
receptor complex, which forms a detection system for Gram-negative
bacteria [
11]. TLR11 was only recently described and responds
to an as yet unknown UPEC-associated molecule [
12].
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Fig. 1. Toll-like receptors: ligands and adaptor molecules. TLRs recognize specific pathogen-associated molecular patterns by homophilic or heterophilic interaction. A subset of nucleic acid-specific TLRs is localized in intracellular endosomes. TLRs signal through a group of cytosolic adaptor molecules that redistribute to the intracellular Toll/interleukin-1 receptor (TIR) domain upon activation of the receptor complex.
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TLR4 and TLR11 signal for renal neutrophil recruitment in mice with UTI
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It has long been known that so-called LPS-hyporesponsive C3H/HeJ
mice lack renal neutrophil recruitment and leukocyturia upon
challenge with UPEC [
13]. After the discovery of the TLR family,
it was noted that the functional defect in LPS-hyporesponsive
C3H/HeJ mice results from a non-functional product of a
Tlr4 gene mutation [
11,
14]. Upon ascending UPEC infection, TLR4 mutant
mice fail to induce renal expression of chemokines that signal
for neutrophil recruitment in UTI, i.e. CXCL2 [
15,
16]. CXCL2,
the murine homologue of interleukin-8 (IL-8), is expressed by
immune cells as well as renal tubular epithelial cells [
15].
We used intravital microscopy in order to test the hypothesis
that TLR4–LPS interaction is required for local neutrophil
recruitment after LPS exposure. Upon challenge with UPEC LPS,
TLR4 mutant mice were found to lack endovascular adhesion and
transendothelial migration of leukocytes [
15]. After local exposure
to CXCL2, TLR4-deficient mice showed normal leukocyte recruitment,
indicating that LPS recognition through TLR4 is a proximal event
in that process.
TLR11 may have a similar role because TLR11-deficient mice, similarly to TLR4 mutants, lack appropriate cellular immunity upon UPEC infection [12]. TLR11 is expressed on cells of the monocyte–macrophage lineage but also at high levels in the healthy mouse kidney [12]. This raises the question of whether intrinsic renal cells, i.e. renal tubular epithelia, signal UPEC infection through TLRs.
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Do intrinsic renal cells signal through TLRs during UPEC infection?
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Epithelial cells represent a structural barrier and functional
interface for pathogen–host interaction during infection
[
17]. Thus, it was hypothesized that TLRs expressed by the epithelial
lining of the lower and upper urinary tract could recognize
UPEC during UTI. Tsuboi
et al. demonstrated that tubular epithelial
cells isolated from TLR4 mutant mice lack CC-chemokine expression
upon exposure to
E.coli LPS [
18]. We generated chimeric mice
by bone marrow cross-transplantation from TLR4 mutant and wild-type
mice in order to determine the contribution of TLR4 on intrinsic
renal cells for neutrophil recruitment in infective pyelonephritis
[
15]. After UPEC infection, mice that lack a functional TLR4
in intrinsic renal cells were unable to signal for neutrophil
recruitment. In these mice, renal abcess formation was absent,
despite high UPEC counts in the kidney. These findings are consistent
with a similar study that identified a role for TLR4 in bladder
epithelia during UTI of the lower urinary tract [
19]. Both studies
also revealed that TLR4 activation on infiltrating haematopoietic
cells is also required for mounting leukocyte recruitment in
UTI [
15,
19]. These data convincingly suggest that TLR4 on intrinsic
renal cells as well as on immune cells directs immunity against
UPEC. In the urinary tract, TLR4 signals for local neutrophil
recruitment as a major mechanism of infection control (
Figure 2).
Apart from TLR4, TLR11 appears to be expressed by renal
tubular epithelial cells in mice. Because TLR11-deficient mice
also show defective immunity in UPEC pyelonephritis, a similar
role for UPEC recognition has been suggested [
12].
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Fig. 2. Proposed working model for UPEC recognition during UTI. UPEC bind to uroepithelia in the lower urinary tract and to renal tubular epithelial cells in the kidney by adhesion through P fimbriae and other factors. Cross-linking of glycosphingolipid receptors with TLR4 overcomes the lack of CD14 in these epithelia. Ligation of the LPS receptor complex (and possibly other TLRs) induces local expression of CXCL2/IL8 as well as activation and upregulation of adhesion molecules on adjacent endothelial cells of peritubular capillaries. Local expression of chemokines and adhesion molecules is followed by local neutrophil recruitment, renal abcess formation and leukocyturia.
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Are data from mouse models relevant for human UTI?
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The relevance of data derived from murine studies for human
UTI remains a matter of debate. Zhang
et al. reported stop codons
in the genomic sequence of TLR11, suggesting that TLR11 might
not be expressed in humans [
12]. TLR4 expression in the human
kidney has also been questioned, because studies with human
kidney carcinoma cells yielded inconsistent results in terms
of TLR4 expression
in vitro [
20,
21]. However, human biopsies
stained for TLR4 revealed expression in epithelial cells lining
the entire human urinary tract, including the renal tubular
epithelium [
22]. Besides TLR4, the LPS receptor complex includes
other proteins such as CD14 and MD-2 [
23,
24]. TLR4, MD-2 and
CD14 are all present on mouse tubular epithelial cells [
18,
25],
but their expression in the human urinary tract is less clear.
Immunostaining for CD14 was found to be negative on biopsies
of the human urinary tract [
22]. However, UPEC LPS can activate
human uroepithelial cells in the absence of CD14 [
21,
26]. In
UPEC, LPS becomes complexed with P fimbriae that interact with
glycosphingolipid receptors on uroepithelia. It has been proposed
that TLR4 may act as a co-receptor for that interaction and
signal despite the absence of CD14 (
Figure 2 [
16]).
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Future directions
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The discovery of TLRs holds great promise for a better understanding
of pathogen-induced immunity and autoimmunity in the field of
nephrology [
27]. In contrast to other organs that are exposed
to huge loads of commensals and pathogens, the urinary tract
is supposed to be sterile. Therefore, it is suspected that TLRs
in the urinary tract represent pathogen detection receptors.
However, the recently discovered role of TLR4 and TLR11 in UTI
raises new questions. The natural ligand for TLR11, a presumed
component of UPEC, is unknown. Do humans express a functional
TLR11? Does TLR11 ligation compete with or contribute to the
effects of TLR4 signalling in UTI? Do genetic polymorphisms
that modulate the functions of TLRs affect the susceptibility
to UTI or asymptomatic bacteriuria? Do other TLRs mediate UPEC
recognition or do other TLRs recognize other uropathogenic microbes,
i.e. Gram-positive bacteria? What factors modulate TLR4 signalling
towards selective neutrophil recruitment, as TLR4 ligation leads
to production of monocyte and T-cell-attracting chemokines?
What is the role of modulatory molecules of TLR signalling?
For example, SIGGIR, the
Tir8 gene product and a negative regulator
of TLR signalling, is expressed at high levels in the kidney
but at low levels in the bladder ([
28], own unpublished observation).
Is UPEC adhesion through fimbriae required before TLR activation
can occur? How do glycosphingolipid receptors and TLRs interact
during UPEC infection? Are their additional modifiers of TLR-mediated
innate immunity in UTI? Tamm-Horsfall protein has been shown
to activate dendritic cells through TLR4 [
29]. Its role in UTI-driven
renal inflammation remains to be studied. UTI is a major medical
problem. A better understanding of pathogen recognition and
immune activation in the urinary tract may enable us to identify
new targets for infection control.
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Acknowledgments
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The work was supported by grants from the Deutsche Forschungsgemeinschaft
(AN 372/4-1) and the Fritz-Thyssen Foundation to H.J.A.
Conflict of interest statement. None declared.
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Introduction
Toll-like receptors are innate...