TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase
Jie Fan, Randall S. Frey, Asrar B. Malik
Jie Fan, Randall S. Frey, Asrar B. Malik
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TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase

Abstract

Interactions of polymorphonuclear neutrophils (PMNs) with endothelial cells may contribute to the activation of endothelial cell responses involved in innate immunity. We explored a novel function of PMN NADPH oxidase in the mechanism of Toll-like receptor-2 (TLR2) upregulation induced by LPS-TLR4 signaling in endothelial cells. We showed that LPS induced TLR2 up-regulation through TLR4- and MyD88-dependent signaling. In neutropenic mice, the LPS-induced NF-kB activation and TLR2 expression were significantly reduced, and both responses were restored upon repletion by PMN obtained from WT mice but not by PMNs from NADPH oxidase gp91phox–/– mice. These findings were recapitulated in mouse lung vascular endothelial cells cocultured with PMNs, indicating that the augmented NF-kB activation and the resultant TLR2 upregulation in endothelial cells were secondary to oxidant signaling generated by PMN NADPH oxidase. The functional relevance of NADPH oxidase in mediating TLR4-induced TLR2 expression in endothelial cells was evident by markedly elevated and stable ICAM-1 expression as well as augmented PMN migration in response to sequential challenge with LPS and peptidoglycan. Thus, PMN NADPH oxidase–derived oxidant signaling is an important determinant of the cross talk between TLR4 and TLR2 and the control of endothelial cell activation.

Authors

Jie Fan, Randall S. Frey, Asrar B. Malik

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Figure 7

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Model of PMN NADPH oxidase–derived oxidant signaling in mediating the TL...
Model of PMN NADPH oxidase–derived oxidant signaling in mediating the TLR4-TLR2 cross talk in endothelial cells. LPS stimulation induces NADPH oxidase activation and production of reactive oxygen species (ROS) in PMNs as well as the initiation of MyD88-dependent NF-κB signaling in endothelial cells and the consequent expression of TLR2 and ICAM-1. Adhesion of PMNs to endothelial cells is mediated by binding of constitutive ICAM-1 to CD18 integrin and provides the appropriate coupling required for PMNs to transmit oxidant signals to endothelial cells. The oxidants augment NF-κB signaling and TLR2 expression (+), which results in the augmented response of the cell to PGN, thereby amplifying ICAM-1 expression (circled +) and promoting stable adhesion of PMNs to endothelial cells and increased PMN migration. Thus, the PMN NADPH oxidase–mediated TLR4-TLR2 cross talk activates a positive feedback signal leading to sustained and amplified endothelial activation in response to invading pathogens.