TNF establish antifungal protection by epithelial TLR4 upregulation

Schaller M., Naglik J.R., Korting H.C., Weind G.

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Immune responsiveness to many pathogens depends on innate recognition molecules known as pattern recognition receptors (PRRs) e.g. Toll-like receptors (TLRs). Infection of a three-dimensional organotypic epithelial model (RHE) with C. albicans suppressed TLR4 signalling despite clear evidence of mucosal injury and pro-inflammatory cytokine response. Integration of polymorphonuclear leukocytes (PMNs) mediated upregulation of epithelial TLR4 and concomitant protection against fungal infection which was independent of physical PMN/epithelial cell contact. Candida invasion and cell injury could be restored by the addition of TLR4 antibodies and TLR4 'knockdown' using RNA interference. The protective phenotype was associated with a pro-inflammatory cytokine release. Blocking of these cytokines with neutralizing antibodies showed the most significant impact on the TLR4 mediated protective effect for TNF. To confirm the important role of this cytokine in the host defence against Candida infections we investigated the role of exogenous TNF for TLR4 expression and protection from fungal invasion in the absence of PMNs. We observed a strong up regulation of TLR4 gene and protein expression after addition of 1 or 10 ng/ml TNF 12 h after infection of the oral RHE. The increased TLR4 expression was associated with a reduced LDH release and protection from fungal invasion. In contrast, addition of TNF to the oral RHE 1h before inoculation with Candida led to increased fungal damage after 24 h compared to the control. Our results point out that activation of cytokine release are crucial for the upregulation of epithelial TLR4 and the subsequent protection from fungal invasion. Among the cytokines tested, TNF seems to have the most significant impact, which confirms the important role of this cytokine in the host defence against systemic Candida

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Full conference title: 

17th International Society for Human and Animal Mycology
    • ISHAM 17th (2009)