Toll-like Receptor 5-Mediated Corneal Epithelial Inflammatory Responses to<i>Pseudomonas aeruginosa</i>Flagellin

Zhang, Jing; Xu, Ke‐Ping; Ambati, Balamurali K.; Yu, Fei

doi:10.1167/iovs.03-0219

Cited by 165 publications

(165 citation statements)

References 33 publications

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“…Activation of TLR2, TLR4, and TLR5 expressed by various epithelia can contribute to host defense by induction of cytokines (9,10,13,14,19,20) and antimicrobial peptides (3,12). In this study we examined the regulated expression and function of TLR5 and TLR9 on keratinocytes, given that our preliminary studies found that TLR5 and TLR9 were expressed in distinct microanatomic locations of the epidermis.…”

Section: Discussionmentioning

confidence: 99%

“…Cytokines, chemokines, and antimicrobial peptides produced by epithelial cells enable them to participate in innate and acquired immune responses (1)(2)(3)(4)(5)(6). In addition, epithelia express certain TLRs, which may contribute to their ability to sense and respond to invading pathogens (3,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

“…TLR9 is activated by unmethylated DNA sequences (CpG dinucleotides) found in bacterial DNA (22)(23)(24). TLR1-5 and TLR9 are expressed in various epithelia (3,(12)(13)(14)(15)(16)(17)(18)(19), including human keratinocytes (7-11, 20, 21).…”

mentioning

confidence: 99%

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TGF-α Regulates TLR Expression and Function on Epidermal Keratinocytes

Miller¹,

Sørensen

Liu³

et al. 2005

The Journal of Immunology

147

117

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The expression of TLRs on epithelial cells provides a first line of defense against invading pathogens. We investigated the regulated expression and function of TLR5 and TLR9 on human keratinocytes, because we found by immunohistochemistry that these TLRs are expressed in distinct layers of the epidermis. We found that TGF-α, a growth and differentiation factor that is present during wound healing and in psoriasis, increased the expression of both TLR5 and TLR9 on keratinocytes. In addition, TGF-α regulated the function of TLR5 and TLR9, because activation with their respective ligands enhanced the production of IL-8 and human β-defensins. These findings provide evidence that TGF-α up-regulates TLR expression and function, augmenting host defense mechanisms at epithelial surfaces.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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TGF-α Regulates TLR Expression and Function on Epidermal Keratinocytes

Miller¹,

Sørensen

Liu³

et al. 2005

The Journal of Immunology

147

117

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“…Corneal epithelial cells are located at the ocular surface, and in addition to providing a physical barrier function, they also mediate the immune response to microbial products through the production of proinflammatory cytokines, chemokines, and antimicrobial peptides (9,10). Furthermore, corneal epithelial cells express several TLRs and can respond in vitro to TLR2, TLR3, and TLR5 agonists (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Our previous studies demonstrated that TLR2, TLR4, and TLR9 are expressed in the cornea and can mediate corneal inflammation through the MyD88 adaptor molecule (19,22).…”

mentioning

confidence: 99%

MyD88 Functions as a Negative Regulator of TLR3/TRIF-induced Corneal Inflammation by Inhibiting Activation of c-Jun N-terminal Kinase

Johnson

Pearlman

2008

Journal of Biological Chemistry

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The adaptor molecule MyD88 is necessary for responses to all Toll-like receptors except TLR3 and a subset of TLR4 signaling events, which are mediated by the adaptor molecule TRIF. To determine the role of TRIF in host inflammatory responses, corneal epithelium of C57BL/6, TLR3 ؊/؊ , TRIF ؊/؊ , and MyD88 ؊/؊ mice was abraded and stimulated with the synthetic TLR3 ligand poly(I:C). We found that poly(I:C) induced a pronounced cellular infiltration into the corneal stroma, which was TLR3-and TRIF-dependent. Unexpectedly, the inflammatory response was exacerbated in MyD88 ؊/؊ mice, with enhanced neutrophil and F4/80 ؉ cell infiltration into the corneal stroma and elevated corneal haze, which is an indicator of loss of corneal transparency. To determine whether MyD88-dependent inhibition of TLR3/TRIF responses is a general phenomenon, we examined cytokine production by MyD88 ؊/؊ bone marrowderived macrophages; however, no significant difference was observed between MyD88 ؉/؉ or MyD88 ؊/؊ macrophages. In contrast, human corneal epithelial cells (HCECs) transfected with MyD88 small interfering RNA had significantly increased (2.5-fold) CCL5/RANTES production compared with control HCECs, demonstrating a negative regulatory role for MyD88 in TLR3/TRIF responses in these cells. Finally, knockdown of MyD88 in HCECs resulted in increased phosphorylation of c-Jun N-terminal kinase (JNK), but not p38, IRF-3, or NF-B. Consistent with this finding, the JNK inhibitor SP600125, but not p38 inhibitor SB203580, ablated this response. Taken together, these findings demonstrate a novel JNK-dependent inhibitory role for MyD88 in the TLR3/TRIF activation pathway.

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“…Some studies have demonstrated the role of the flagellin of P. aeruginosa in induction of IL-6 and TNFα [24,28] or CXCL8 [37,38] during mouse infections. In this work, the inflammatory response following human keratinocyte and RHE infection with flagellin-deficient strains was strongly decreased.…”

Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa flagellum is critical for invasion, cutaneous persistence and induction of inflammatory response of skin epidermis

Garcia

Morello

Garnier³

et al. 2018

Virulence

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Pseudomonas aeruginosa, an opportunistic pathogen involved in skin and lung diseases, possesses numerous virulence factors, including type 2 and 3 secretion systems (T2SS and T3SS) and its flagellum, whose functions remain poorly known during cutaneous infection. Using isogenic mutants deleted from genes encoding each or all of these three virulence factors, we investigated their role in induction of inflammatory response and in tissue invasiveness in human primary keratinocytes and reconstructed epidermis. Our results showed that flagellum, but not T2SS and T3SS, is involved in induction of a large panel of cytokine, chemokine, and antimicrobial peptide (AMP) mRNA in the infected keratinocytes. Chemokine secretion and AMP tissular production were also dependent on the presence of the bacterial flagellum. This pro-inflammatory effect was significantly reduced in keratinocytes infected in presence of anti-toll-like receptor 5 (TLR5) neutralizing antibody. Bacterial invasion of human epidermis and persistence in a mouse model of sub-cutaneous infection were dependent on the P. aeruginosa flagellum. We demonstrated that flagellum constitutes the main virulence factor of P. aeruginosa involved not only in early induction of the epidermis inflammatory response but also in bacterial invasion and cutaneous persistence. P. aeruginosa is mainly sensed by TLR5 during the early innate immune response of human primary keratinocytes.

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Toll-like Receptor 5-Mediated Corneal Epithelial Inflammatory Responses toPseudomonas aeruginosaFlagellin

Abstract: Flagellin of Gram-negative pathogens such as PA contributes to the inflammatory responses of corneal epithelium in a TLR5-NF-kappaB signaling pathway-dependent manner.

Cited by 165 publications

References 33 publications

TGF-α Regulates TLR Expression and Function on Epidermal Keratinocytes

TGF-α Regulates TLR Expression and Function on Epidermal Keratinocytes

MyD88 Functions as a Negative Regulator of TLR3/TRIF-induced Corneal Inflammation by Inhibiting Activation of c-Jun N-terminal Kinase

Pseudomonas aeruginosa flagellum is critical for invasion, cutaneous persistence and induction of inflammatory response of skin epidermis

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