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Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling
Günther Weindl, … , Hans Christian Korting, Martin Schaller
Günther Weindl, … , Hans Christian Korting, Martin Schaller
Published November 8, 2007
Citation Information: J Clin Invest. 2007;117(12):3664-3672. https://doi.org/10.1172/JCI28115.
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Research Article Immunology

Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling

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Abstract

Mammalian TLRs are central mediators of the innate immune system that instruct cells of the innate and adaptive response to clear microbial infections. Here, we demonstrate that human epithelial TLR4 directly protected the oral mucosa from fungal infection via a process mediated by polymorphonuclear leukocytes (PMNs). In an in vitro epithelial model of oral candidiasis, the fungal pathogen Candida albicans induced a chemoattractive and proinflammatory cytokine response but failed to directly modulate the expression of genes encoding TLRs. However, the addition of PMNs to the C. albicans–infected model strongly upregulated cytoplasmic and cell-surface epithelial TLR4 expression, which correlated directly with protection against fungal invasion and cell injury. C. albicans invasion and cell injury was restored by the addition of TLR4-specific neutralizing antibodies and knockdown of TLR4 using RNA interference, even in the presence of PMNs, demonstrating the direct role of epithelial TLR4 in the protective process. Furthermore, treatment with neutralizing antibodies specific for TNF-α resulted in strongly reduced TLR4 expression accompanied by augmented epithelial cell damage and fungal invasion. To our knowledge, this is the first description of such a PMN-dependent, TLR4-mediated protective mechanism at epithelial surfaces, which may provide significant insights into how microbial infections are managed and controlled in the oral mucosa.

Authors

Günther Weindl, Julian R. Naglik, Susanne Kaesler, Tilo Biedermann, Bernhard Hube, Hans Christian Korting, Martin Schaller

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Figure 4

Cell surface TLR4 directly recognizes C. albicans and is expressed intracellularly.

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Cell surface TLR4 directly recognizes C. albicans and is expressed intra...
Electron microscopy with postembedding immunogold labeling in C. albicans–infected oral RHE at 24 h in the presence of PMNs. (A) Expression of TLR4 was evident at the site of direct host-pathogen contact. (B) Higher-magnification view of boxed region in A. (C) An epithelial cell inside the oral RHE. (D) Higher-magnification view of boxed region in C revealed expression of TLR4 at the cell membrane and intracellularly. Arrows indicate gold-labeled TLR4 expression. Data are representative of 3 independent experiments. Original magnification, ×20,000 (A and B); ×3,000 (C and D).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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