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Differential responses of mast cell Toll-like receptors 2 and 4 in allergy and innate immunity
Volaluck Supajatura, … , Chisei Ra, Hideoki Ogawa
Volaluck Supajatura, … , Chisei Ra, Hideoki Ogawa
Published May 15, 2002
Citation Information: J Clin Invest. 2002;109(10):1351-1359. https://doi.org/10.1172/JCI14704.
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Article Immunology

Differential responses of mast cell Toll-like receptors 2 and 4 in allergy and innate immunity

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Abstract

Toll-like receptor 2 (TLR2) and TLR4 play important roles in the early innate immune response to microbial challenge. To clarify the functional roles of TLRs 2 and 4 in mast cells, we examined bone marrow–derived mast cells (BMMCs) from TLR2 or TLR4 gene-targeted mice. Peptidoglycan (PGN) from Staphylococcus aureus stimulated mast cells in a TLR2-dependent manner to produce TNF-α, IL-4, IL-5, IL-6, and IL-13, but not IL-1β. In contrast, LPS from Escherichia coli stimulated mast cells in a TLR4-dependent manner to produce TNF-α, IL-1β, IL-6, and IL-13, but not IL-4 nor IL-5. Furthermore, TLR2- but not TLR4-dependent mast cell stimulation resulted in mast cell degranulation and Ca2+ mobilization. In a mast cell–dependent model of acute sepsis, TLR4 deficiency of BMMCs in mice resulted in significantly higher mortality because of defective neutrophil recruitment and production of proinflammatory cytokines in the peritoneal cavity. Intradermal injection of PGN led to increased vasodilatation and inflammation through TLR2-dependent activation of mast cells in the skin. Taken together, these results suggest that direct activation of mast cells via TLR2 or TLR4 by respective microligands contributes to innate and allergic immune responses.

Authors

Volaluck Supajatura, Hiroko Ushio, Atsuhito Nakao, Shizuo Akira, Ko Okumura, Chisei Ra, Hideoki Ogawa

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Figure 5

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TLR2 on mast cell–dependent skin inflammation upon application of PGN. R...
TLR2 on mast cell–dependent skin inflammation upon application of PGN. Reconstitution of skin mast cells of W/Wv mice by TLR2–/–, TLR4–/–, or wild-type BMMCs was done as described in Methods. Wild-type mice (a) or indicated mice (b) were intravenously injected with 0.5% Evans blue 5 minutes before intradermal application and 20 μl of PGN (100 μg/ml) or LPS (100 ng/ml) into the left ear or saline into the right ear. The mice were sacrificed 15 minutes after PGN or LPS injection, and dye contents in the tissues were measured as described in Methods. Data shown are mean ± SD of three mice. (c) Reconstitution of skin mast cells of W/Wv mice by TLR2–/–, TLR4–/–, or wild-type BMMCs was histologically confirmed by Alcian blue and Safranin staining (AS; without any treatment; upper panels) and Toluidine blue staining (TB; saline-injected; lower panels). (d) Mice were intradermally injected with PGN (upper four rows) or LPS (bottom row) as described above. Mice were sacrificed 15 minutes (left and middle columns) or 4 hours later (right column), and ear sections from W/Wv (first row), W/Wv/wild-type (W/Wv/WT; second row), W/Wv/TLR4–/– (third row), or W/Wv/TLR2–/– mice (fourth row) were stained with H&E (middle and right columns) or Toluidine blue (TB; left column) for histological evaluations. All magnification is ×600, except the figures at 4 hours after PGN application from W/Wv/WT and W/Wv/TLR4–/– and at 4 hours after LPS application (all ×200).

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