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TXA2 attenuates allergic lung inflammation through regulation of Th2, Th9, and Treg differentiation
Hong Li, … , Thomas M. Coffman, Darryl C. Zeldin
Hong Li, … , Thomas M. Coffman, Darryl C. Zeldin
Published March 14, 2024
Citation Information: J Clin Invest. 2024;134(9):e165689. https://doi.org/10.1172/JCI165689.
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Research Article Immunology Pulmonology Article has an altmetric score of 3

TXA2 attenuates allergic lung inflammation through regulation of Th2, Th9, and Treg differentiation

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Abstract

In lung, thromboxane A2 (TXA2) activates the TP receptor to induce proinflammatory and bronchoconstrictor effects. Thus, TP receptor antagonists and TXA2 synthase inhibitors have been tested as potential asthma therapeutics in humans. Th9 cells play key roles in asthma and regulate the lung immune response to allergens. Herein, we found that TXA2 reduces Th9 cell differentiation during allergic lung inflammation. Th9 cells were decreased approximately 2-fold and airway hyperresponsiveness was attenuated in lungs of allergic mice treated with TXA2. Naive CD4+ T cell differentiation to Th9 cells and IL-9 production were inhibited dose-dependently by TXA2 in vitro. TP receptor–deficient mice had an approximately 2-fold increase in numbers of Th9 cells in lungs in vivo after OVA exposure compared with wild-type mice. Naive CD4+ T cells from TP-deficient mice exhibited increased Th9 cell differentiation and IL-9 production in vitro compared with CD4+ T cells from wild-type mice. TXA2 also suppressed Th2 and enhanced Treg differentiation both in vitro and in vivo. Thus, in contrast to its acute, proinflammatory effects, TXA2 also has longer-lasting immunosuppressive effects that attenuate the Th9 differentiation that drives asthma progression. These findings may explain the paradoxical failure of anti-thromboxane therapies in the treatment of asthma.

Authors

Hong Li, J. Alyce Bradbury, Matthew L. Edin, Artiom Gruzdev, Huiling Li, Joan P. Graves, Laura M. DeGraff, Fred B. Lih, Chiguang Feng, Erin R. Wolf, Carl D. Bortner, Stephanie J. London, Matthew A. Sparks, Thomas M. Coffman, Darryl C. Zeldin

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Figure 5

TXA2 inhibits promotion of Th9 cell differentiation by DCs in vitro.

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TXA2 inhibits promotion of Th9 cell differentiation by DCs in vitro.
(A)...
(A) Coculture of purified naive CD4+CD62L+ T cells with CD11c+ DCs (from lung) enhanced Th9 cell differentiation compared with naive T cells alone. Treatment with 300 nM cTXA2 significantly impaired Th9 cell differentiation of naive T cells, whether cultured alone or in the presence of DCs. n = 10 per group, *P < 0.05. (B) Purified naive CD4+CD62L+ T cells or CD11c+, CD11c+F4/80+, and F4/80+ myeloid cells were treated with vehicle or LPS (1 mg/mL) in vitro, and supernatants were assayed for TXB2 by liquid chromatography–tandem mass spectrometry. (C) Purified CD11c+ or naive CD4+ T cells were treated with vehicle or LPS (1 mg/mL) in vitro. LPS treatment increased TP receptor (Tbxa2r) mRNA levels in CD4+ T cells and TXA2 synthase (Tbxas1) mRNA levels in CD11c+ cells. n = 3 per group, *P < 0.05. (D and E) Mixed cultures of CD11c+ and CD4+ T cells (D) or Transwell-separated CD11c+ and CD4+ T cells (E) were incubated with vehicle, cTXA2, and TGF-β plus IL-4 as indicated and assayed for Tbxa2r and Tbxas1 mRNA levels. n = 9, *P < 0.05. Significance was evaluated by 1-way ANOVA for A and D and multiple t tests for B, C, and E.

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

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