Staphylococcal lipoteichoic acid inhibits delayed-type hypersensitivity reactions via the platelet-activating factor receptor
Qiwei Zhang, … , Takao Shimizu, Jeffrey B. Travers
Qiwei Zhang, … , Takao Shimizu, Jeffrey B. Travers
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2855-2861. https://doi.org/10.1172/JCI25429.
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Staphylococcal lipoteichoic acid inhibits delayed-type hypersensitivity reactions via the platelet-activating factor receptor

Abstract

Staphylococcus aureus infections are known triggers for skin inflammation and can modulate immune responses. The present studies used model systems consisting of platelet-activating factor receptor–positive and –negative (PAF-R–positive and –negative) cells and PAF-R–deficient mice to demonstrate that staphylococcal lipoteichoic acid (LTA), a constituent of Gram-positive bacteria cell walls, acts as a PAF-R agonist. We show that LTA stimulates an immediate intracellular Ca2+ flux only in PAF-R–positive cells. Intradermal injections of LTA and the PAF-R agonist 1-hexadecyl-2-N-methylcarbamoyl glycerophosphocholine (CPAF) induced cutaneous inflammation in wild-type but not PAF-R–deficient mice. Systemic exposure to LTA or CPAF inhibited delayed-type hypersensitivity (DTH) reactions to the chemical dinitrofluorobenzene only in PAF-R–expressing mice. The inhibition of DTH reactions was abrogated by the addition of neutralizing antibodies to IL-10. Finally, we measured levels of LTA that were adequate to stimulate PAF-R in vitro on the skin of subjects with infected atopic dermatitis. Based on these studies, we propose that LTA exerts immunomodulatory effects via the PAF-R through production of the Th2 cytokine IL-10. These findings show a novel mechanism by which staphylococcal infections can inhibit Th1 reactions and thus worsen Th2 skin diseases, such as atopic dermatitis.

Authors

Qiwei Zhang, Nico Mousdicas, Qiaofang Yi, Mohammed Al-Hassani, Steven D. Billings, Susan M. Perkins, Katherine M. Howard, Satoshi Ishii, Takao Shimizu, Jeffrey B. Travers

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Figure 4

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Involvement of IL-10 in PAF-R–mediated suppression of DTH. (A) Effect of...
Involvement of IL-10 in PAF-R–mediated suppression of DTH. (A) Effect of CPAF or LTA injection on epidermal IL-10 levels. Dorsal sides of ears of wild-type or PAF-R–/– mice were injected with 100 ng CPAF, 10 μg LTA, or vehicle control and the tissue harvested at various times. Immunohistochemistry was used to measure epidermal IL-10 levels. Depicted are representative sections 72 hours after treatment with CPAF, LTA, or vehicle control. Magnification, ×400. (B) Effect of a neutralizing anti–IL-10 antibody on CPAF-mediated inhibition of DTH reactions. Wild-type mice were injected with 250 ng CPAF or BSA vehicle control i.p.; 4 and 24 hours later, the mice were injected i.p. with 100 μg neutralizing rat anti-mouse IL-10 or 100 μg rat IgG1 or BSA vehicle. Five days later, the mice were sensitized with DNFB, then 9 days later challenged by painting DNFB on 1 ear and vehicle control on the other. Punch biopsies were performed and specimens weighed 24 hours later. The data represent the mean ± SD difference in ear specimen weights from 7–8 mice. *Statistically significant (P < 0.05) inhibition of DNFB-mediated DTH by CPAF treatment. It should be noted that treatment with a neutralizing anti–IL-10 antibody but not isotype IgG1 antibody control abolished CPAF-mediated inhibition of DTH reaction.