Neutrophil Recruitment and Resistance to Urinary Tract Infection

Haraoka, Masashi; Hang, Long; Frendéus, Björn; Godaly, Gabriela; Burdick, Marie D.; Strieter, Robert M.; Svanborg, Catharina

doi:10.1086/315006

Cited by 244 publications

(258 citation statements)

References 28 publications

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“…Neutrophil recruitment to the urinary tract was used to quantify the innate host response as the chemotactic signal for the neutrophils is derived from the epithelial cells, after activation by pathogenic bacteria which adhere to the luminal side of the mucosa [27,28]. Mice differing in Tlr4 or Tlr2 genotype were intra-vesically inoculated with the pap+ or the pap-E. coli S1918 derivatives (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

et al. 2006

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The mucosal host defence discriminates pathogens from commensals, and prevents infection while allowing the normal flora to persist. Paradoxically, Toll-like receptors (TLR) control the mucosal defence against pathogens, even though the TLR recognise conserved molecules like LPS, which are shared between pathogens and commensals. This study proposes a mechanism of pathogen-specific mucosal TLR4 activation, involving adhesive ligands and their host cell receptors. TLR4 signalling was activated in CD14-negative, LPS-unresponsive epithelial cells by P fimbriated, uropathogenic Escherichia coli but not by a mutant lacking fimbriae. Epithelial TLR4 signalling in vivo involved the glycosphingolipid receptors for P fimbriae and the adaptor proteins Toll/IL-1R (TIR) domain-containing adaptor inducing IFN-b (TRIF)/TRIF-related adaptor molecule (TRAM), but myeloid differentiation protein 88 (MyD88)/TIR domain-containing adaptor protein were not required for the epithelial response. Substituting the P fimbriae with type 1 fimbriae changed TLR4 signalling from the TRIF to the MyD88 adaptor pathway. In addition, the adaptor proteins and the fimbrial type were found to influence bacterial clearance. Trif -/-and Tram -/-mice remained infected with P fimbriated E. coli but cleared thetype 1 fimbriated strain, while Myd88 -/-mice became carriers of both the P and the type 1 fimbriated bacteria. Thus, TLR4 may be engaged specifically by pathogens, when the proper cell surface receptors are engaged by virulence ligands. IntroductionToll-like receptors (TLR) control the innate host defence at mucosal surfaces and yet commensals do not induce an inflammatory response at those sites. The relative inertia to the commensals is paradoxical, as the TLR recognise conserved pathogen-associated molecular patterns (PAMP), which are present on both pathogenic and commensal bacteria. Lipolysaccharide (LPS), flagellin, peptidoglycan or DNA may bind directly to the TLR but in addition, co-receptors are needed to enhance the TLR response to these conserved ligands [1][2][3]. Myeloid cells use CD14 and MD-2 as co-receptors for LPS in TLR4 signalling, and minute amounts of LPS may elicit a strong systemic inflammatory response [4,5]. However, the TLR response to pathogen attack at mucosal surfaces is controlled by different interactions. Epithelial cells must be protected from constant TLR activation by commensals and their PAMP, in order for mucosal integrity to be maintained. The epithelial cells thus lack co-receptors like CD14 [6][7][8][9][10][11], and in addition, commensals have been suggested to actively suppress epithelia responses through NF-jB [12,13]. Yet, mucosal pathogens evoke rapid TLR4-dependent responses at mucosal sites, suggesting that alternative ligands and receptors might be involved in mucosal TLR activation. Pathogens use adhesive surface ligands to break the inertia of the mucosal barrier [14][15][16]. The innate defence is activated as a direct result of these interactions and epithelial cells produce the first wave of me...

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Section: Resultsmentioning

confidence: 99%

Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

et al. 2006

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“…However, the two UPEC strains induced markedly different stimulation profiles of proinflammatory mediators in the kidneys of Lps n and Lps d mice, suggesting that different bacterial factors produced by the UPECs may be implicated in the activation of distinct TLR4-dependent and -independent signaling pathways. MIP-2 and its human counterpart IL-8 play key roles in the migration of neutrophils to infected mucosal sites to protect them against invading pathogens (41,42,57). The two UPECs stimulated MIP-2 mRNA expression and protein secretion in both Lps n kidney and cultured Lps n MCDs through a main TLR4-dependent pathway.…”

Section: Discussionmentioning

confidence: 99%

“…MIP-2 is required for neutrophil passage across the epithelial barrier of the infected urinary tract in experimental models of UTI (41,42). The question arises of whether collecting duct cells may attract leukocytes by secreting chemokines toward their basal (i.e., interstitium) and/or apical (i.e., tubule lumen) sides.…”

Section: Interaction Between Upec Isolates and The Apical Membranes Omentioning

confidence: 99%

Renal Collecting Duct Epithelial Cells React to Pyelonephritis-Associated Escherichia coli by Activating Distinct TLR4-Dependent and -Independent Inflammatory Pathways

Chassin

Goujon

Darche³

et al. 2006

The Journal of Immunology

119

156

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TLR4 plays a central role in resistance to pyelonephritis caused by uropathogenic Escherichia coli (UPEC). It has been suggested that renal tubule epithelial cells expressing TLRs may play a key role in inflammatory disorders and in initiating host defenses. In this study we used an experimental mouse model of ascending urinary tract infection to show that UPEC isolates preferentially adhered to the apical surface of medullary collecting duct (MCD) intercalated cells. UPEC-infected C3H/HeJ (Lpsd) mice carrying an inactivating mutation of tlr4 failed to clear renal bacteria and exhibited a dramatic slump in proinflammatory mediators as compared with infected wild-type C3H/HeOuJ (Lpsn) mice. However, the level of expression of the leukocyte chemoattractants MIP-2 and TNF-α still remained greater in UPEC-infected than in naive C3H/HeJ (Lpsd) mice. Using primary cultures of microdissected Lpsn MCDs that expressed TLR4 and its accessory molecules MD2, MyD88, and CD14, we also show that UPECs stimulated both a TLR4-mediated, MyD88-dependent, TIR domain-containing adaptor-inducing IFN-β-independent pathway and a TLR4-independent pathway, leading to bipolarized secretion of MIP-2. Stimulation by UPECs of the TLR4-mediated pathway in Lpsn MCDs leads to the activation of NF-κB, and MAPK p38, ERK1/2, and JNK. In addition, UPECs stimulated TLR4-independent signaling by activating a TNF receptor-associated factor 2-apoptosis signal-regulatory kinase 1-JNK pathway. These findings demonstrate that epithelial collecting duct cells are actively involved in the initiation of an immune response via several distinct signaling pathways and suggest that intercalated cells play an active role in the recognition of UPECs colonizing the kidneys.

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“…In the case of the pulmonary system, mucosal inflammation may be manifest as pneumonitis, pneumonia, or asthma (5-7), acute and chronic pulmonary conditions that have a high degree of morbidity and potential mortality. And in the case of the urinary tract, mucosal inflammation may be manifest as interstitial nephritis, cystitis, and urethritis (8)(9)(10), causes of significant morbidity in patients of all ages. To elucidate the pathogenesis of mucosal inflammatory diseases, research over the past several decades has focused on the role of the immune system in their developmentin particular the relationship between mucosal lymphocytes, macrophages, and neutrophils, and the effects of their cellular by-products on mucosal integrity and function (11)(12)(13).…”

Section: The Clinical and Scientific Importance Of Mucosal Inflammationmentioning

confidence: 99%

No Longer an Innocent Bystander: Epithelial Toll-Like Receptor Signaling in the Development of Mucosal Inflammation

Gribar

Richardson

Sodhi

et al. 2008

Mol Med

142

109

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Diseases of mucosal inflammation represent important causes of morbidity and mortality, and have led to intense research efforts to understand the factors that lead to their development. It is well accepted that a breakdown of the normally impermeant epithelial barrier of the intestine, the lung, and the kidney is associated with the development of inflammatory disease in these organs, yet significant controversy exists as to how this breakdown actually occurs, and how such a breakdown may lead to inflammation. In this regard, much work has focused upon the role of the epithelium as an "innocent bystander," a target of a leukocyte-mediated inflammatory cascade that leads to its destruction in the mucosal inflammatory process. However, recent evidence from a variety of laboratories indicates that the epithelium is not merely a passive component in the steps that lead to mucosal inflammation, but is a central participant in the process. In addressing this controversy, we and others have determined that epithelial cells express Toll-like receptors (TLRs) of the innate immune system, and that activation of TLRs by endogenous and exogenous ligands may play a central role in determining the balance between a state of "mucosal homeostasis," as is required for optimal organ function, and "mucosal injury," leading to mucosal inflammation and barrier breakdown. In particular, activation of TLRs within intestinal epithelial cells leads to the development of cellular injury and impairment in mucosal repair in the pathogenesis of intestinal inflammation, while activation of TLRs in the lung and kidney may participate in the development of pneumonitis and nephritis respectively. Recent work in support of these concepts is extensively reviewed, while essential areas of further study that are required to determine the significance of epithelial TLR signaling during states of health and disease are outlined.

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Neutrophil Recruitment and Resistance to Urinary Tract Infection

Cited by 244 publications

References 28 publications

Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

Renal Collecting Duct Epithelial Cells React to Pyelonephritis-Associated Escherichia coli by Activating Distinct TLR4-Dependent and -Independent Inflammatory Pathways

No Longer an Innocent Bystander: Epithelial Toll-Like Receptor Signaling in the Development of Mucosal Inflammation

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