Type 1 fimbriae deliver an LPS‐ and TLR4‐dependent activation signal to CD14‐negative cells

Hedlund, Maria; Frendéus, Björn; Wachtler, Caroline; Hang, Long; Fischer, Hans; Svanborg, Catharina

doi:10.1046/j.1365-2958.2001.02205.x

Cited by 118 publications

(115 citation statements)

References 41 publications

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“…On the other hand, the first cells with which the HSV-2 virions come in contact and establish infection are the vaginal epithelial cells. Previous studies have demonstrated that certain TLRs are expressed by epithelial cells lining various body cavities (35)(36)(37)(38), and pathogen recognition by the stromal cells can result in inflammatory responses after bacterial stimulation (39,40). We hypothesized that viral recognition by stromal cells might contribute to the development of the adaptive immune responses.…”

Section: Tlr Recognition Of Viral Infection By Hematopoietic and Stromentioning

confidence: 97%

Induction of antiviral immunity requires Toll-like receptor signaling in both stromal and dendritic cell compartments

Sato

Iwasaki

2004

Proc. Natl. Acad. Sci. U.S.A.

105

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Section: Tlr Recognition Of Viral Infection By Hematopoietic and Stromentioning

confidence: 97%

Induction of antiviral immunity requires Toll-like receptor signaling in both stromal and dendritic cell compartments

Sato

Iwasaki

2004

Proc. Natl. Acad. Sci. U.S.A.

105

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“…Thus, our data do not currently dissipate the debate that exists concerning the expression and role of CD14 in LPS-induced lung epithelial activation. Several authors proposed that these cells are CD14-negative (39,40), while others demonstrated both CD14 mRNA and cell surface protein in human airway epithelial cells (2,18,19). In fact, these contradictory results may be explained by distinct basal activation or differentiation state of the epithelial cells used throughout these investigations.…”

Section: Fig 7 Activation Of Pulmonary Epithelial Cells By Lps Invomentioning

confidence: 99%

Response of Human Pulmonary Epithelial Cells to Lipopolysaccharide Involves Toll-like Receptor 4 (TLR4)-dependent Signaling Pathways

Guillot¹,

Medjane²,

Le-Barillec

et al. 2004

Journal of Biological Chemistry

330

254

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Pulmonary epithelial cells are continuously exposed to microbial challenges as a result of breathing. It is recognized that immune myeloid cells express Toll-like receptors (TLRs), which play a major role in detecting microbes and initiating innate immune responses. In contrast, little is known concerning the expression of TLR in pulmonary epithelial cells per se, their distribution within the cell, their function, and the signaling pathways involved. In this work, we demonstrated by reverse transcription-PCR and/or immunoblot that TLR4 and the accessory molecule MD-2 are constitutively expressed in distinct human alveolar and bronchial epithelial cells. We further characterized by flow cytometry, biotinylation/precipitation, and confocal microscopy the intracellular localization of TLR4 in these cells. Despite this intracellular compartmentalization of TLR4, pulmonary epithelial cells were responsive to the TLR4 activator lipopolysaccharide (LPS), a potent Gram-negative bacteria-associated molecular pattern. Using respiratory epithelial cells isolated from TLR4 knock-out and wild type mice, we demonstrated that TLR4 is the actual activating receptor for LPS in these cells. Furthermore we showed that this cell response to LPS involves a signaling complex including the kinases interleukin-1 receptor-associated kinase (IRAK), p38, Jnk, and ERK1/2. Moreover, using vectors expressing dominant-negative forms of MyD88 and TRAF6, we established that LPS-induced activation of respiratory epithelial cells is largely dependent on TLR4 signaling intermediates. Altogether these data demonstrate that TLR4 is a key element in the response of pulmonary epithelial cells to molecules derived from Gram-negative bacteria. The intracellular localization of TLR4 in lung epithelia is expected to play an important role in the prevention of the development of chronic inflammatory disease.

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“…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.…”

Section: Introductionmentioning

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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Type 1 fimbriae deliver an LPS‐ and TLR4‐dependent activation signal to CD14‐negative cells

Cited by 118 publications

References 41 publications

Induction of antiviral immunity requires Toll-like receptor signaling in both stromal and dendritic cell compartments

Induction of antiviral immunity requires Toll-like receptor signaling in both stromal and dendritic cell compartments

Response of Human Pulmonary Epithelial Cells to Lipopolysaccharide Involves Toll-like Receptor 4 (TLR4)-dependent Signaling Pathways

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

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