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

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

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 9

TXA2 alters expression/binding of PBX1 and NFE2 to the Il9 promoter.

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TXA2 alters expression/binding of PBX1 and NFE2 to the Il9 promoter. (A)...
(A) The locations of transcription factor binding sites in the mouse proximal Il9 promoter. Conservation analysis and motif prediction were used to identify unique binding sites for NFE2 (–150 bp), PBX1 (–481 bp), CREB (–101 bp), PU.1 (–450 bp, –192 bp), and IRF4 (–237 bp) transcription factors relative to the transcription start site (TSS). (B) Naive T cells were treated with TGF-β and IL-4 to induce Th9 cell differentiation in the presence or absence of cTXA2, and expression of Irf4, Pbx1, Nfe2, Creb, and Il9 mRNAs was determined by qPCR. n = 9, *P < 0.05. (C) ChIP-PCR assays of PBX1 and NFE2 binding to genomic DNA from naive T cells during Th9 cell differentiation with or without treatment with cTXA2. DNA fragments were pulled down with anti-NFE2, anti-PBX1, or IgG control antibodies, and NFE2- and PBX1-bound DNA was amplified using specific primers by qPCR. The percentage pull-down by NFE2 or PBX1 relative to input DNA is shown. The locations of ChIP-qPCR primers relative to the TSS (+1) and PBX1 or NFE2 binding sites are shown. n = 3, *P < 0.05. Significance was determined by 1-way ANOVA for B and multiple t tests for C.