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BLT1 in dendritic cells promotes Th1/Th17 differentiation and its deficiency ameliorates TNBS-induced colitis

Cellular & Molecular Immunology volume 15, pages 1047–1056 (2018)Cite this article

Abstract

Leukotriene B4 (LTB4) synthesis is enhanced in the colonic mucosa in patients with inflammatory bowel disease (IBD). BLT1, a high-affinity receptor for LTB4, exhibits no effect on the progression of dextran sodium sulfate (DSS)-induced colitis, which mostly relies on innate immunity. Here, we reported that BLT1 regulates trinitrobenzene sulfonic acid (TNBS)-induced colitis, which reflects CD4+ T-cell-dependent adaptive immune mechanisms of IBD. We found that BLT1 signaling enhanced the progression of colitis through controlling the production of proinflammatory cytokines by dendritic cells (DCs) and modulating the differentiation of Th1 and Th17. BLT1−/− mice displayed an alleviated severity of TNBS-induced colitis with reduced body weight loss and infiltrating cells in the lamina propria. BLT1 deficiency in DCs led to reduced production of proinflammatory cytokines, including IL-6, TNF-α, and IL-12, and these results were further confirmed via treatment with a BLT1 antagonist. The impaired cytokine production by BLT1−/− DCs subsequently led to reduced Th1 and Th17 differentiation both in vitro and in vivo. We further performed a conditional DC reconstitution experiment to assess whether BLT1 in DCs plays a major role in regulating the pathogenesis of TNBS-induced colitis, and the results indicate that BLT1 deficiency in DCs also significantly reduces disease severity. The mechanistic study demonstrated that BLT1-regulated proinflammatory cytokine production through the Gαi βγ subunit-phospholipase Cβ (PLCβ)-PKC pathway. Notably, we found that treatment with the BLT1 antagonist also reduced the production of proinflammatory cytokines by human peripheral blood DCs. Our findings reveal the critical role of BLT1 in regulating adaptive immunity and TNBS-induced colitis, which further supports BLT1 as a potential drug target for adaptive immunity-mediated IBD.

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Acknowledgements

This work was supported by grants from the Ministry of Science and Technology of China (2014CB541903), the National Natural Science Foundation of China (31171348 and 31371414), and the Fundamental Research Funds for the Central Universities.

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  1. These authors contributed equally: Jinfeng Zhou, Weiming Lai.

Authors and Affiliations

  1. Putuo District People’s Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China

    Jinfeng Zhou, Weiming Lai, Wanjie Yang, Yingying Cai, Cuixia Yang, Ningjia Ma, Yue Zhang, Ru Zhang, Xin Xie, Yuan Gao & Changsheng Du

  2. Tongji Hospital of Tongji University branch, Tongji University, Shanghai, 200092, China

    Juping Pan & Hu Shen

  3. CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Xin Xie

  4. Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100086, China

    Zhongjun Dong

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Correspondence to Yuan Gao or Changsheng Du.

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Zhou, J., Lai, W., Yang, W. et al. BLT1 in dendritic cells promotes Th1/Th17 differentiation and its deficiency ameliorates TNBS-induced colitis. Cell Mol Immunol 15, 1047–1056 (2018). https://doi.org/10.1038/s41423-018-0030-2

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