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DcR3 suppresses influenza virus-induced macrophage activation and attenuates pulmonary inflammation and lethality

Journal of Molecular Medicine volume 93, pages 1131–1143 (2015)Cite this article

Abstract

Influenza A virus (IAV) infects macrophages and stimulates innate immunity receptors and sensors to produce proinflammatory cytokines and chemokines, which are responsible for IAV-induced pulmonary inflammation and injury. Decoy receptor 3 (DcR3) is a soluble protein belonging to the tumor necrosis factor receptor superfamily (TNFRSF), and is able to skew macrophage differentiation into an M2 phenotype. We demonstrated that DcR3 attenuated IAV-induced secretion of proinflammatory cytokines and chemokine from macrophages, and mitigated pulmonary infiltration and reduce lethality. Proteome-wide phosphoproteomic mapping revealed that DcR3 not only activated STK10, a negative regulator of cell migration, but also inactivated PKC-α, which are crucial for the activation of ERK and JNK in human macrophages. Furthermore, less pulmonary infiltration with lower levels of proinflammatory cytokines and chemokine in bronchoalveolar lavage fluid (BALF) were observed in DcR3-transgenic mice. Moreover, recombinant DcR3.Fc and heparan sulfate proteoglycan binding domain of DcR3.Fc (HBD.Fc) fusion proteins attenuated weight loss and protected mice from IAV-induced lethality. Thus, DcR3-mediated protection is not only via suppression of proinflammatory cytokine and chemokine release, but also via activation of STK10 to inhibit cell infiltration. DcR3 fusion proteins may become therapeutic agents to protect host from IAV-induced lethality in the future.

Key message

• DcR3 suppresses IAV-induced cytokine secretion.

• DcR3 inhibits IAV-induced JNK and ERK activation in human macrophages.

• DcR3 downregulates TLR3 and 7 expressions in human macrophages.

• DcR3 protects mice from IAV-induced lethality.

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Acknowledgments

We thank Wei-Ru Huang for technical assistance and Dr. Shin-Ru Shih and Dr. Adolfo García-Sastre for providing influenza viruses A/Taiwan/3530/2001 (H1N1) and A/Puerto Rico/8/34 (H1N1; PR/8), respectively. This work was supported by the National Science Council (NSC 103-2321-B-001-044 and NSC 103-2320-B-001-010-MY3), and Summit and Thematic Research Project (AS-101-TP-B06-2) of Academia Sinica.

Conflict of interest

The authors declare no competing financial interests.

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Affiliations

  1. Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan

    Ming-Ting Huang & Shie-Liang Hsieh

  2. Department of Microbiology and Immunology, School of Medicine, Taipei Medical University, Taipei, Taiwan

    Szu-Ting Chen

  3. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

    Szu-Ting Chen, Teh-Ying Chou & Shie-Liang Hsieh

  4. Institute of Chemistry, Academia Sinica, Taipei, Taiwan

    Hsin-Yi Wu & Yu-Ju Chen

  5. Genomics Research Center, Academia Sinica, 128, Academia Road, Sec. 2, Nankang District, Taipei, 115, Taiwan

    Yu-Ju Chen & Shie-Liang Hsieh

  6. Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Teh-Ying Chou

  7. Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

    Shie-Liang Hsieh

  8. Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan

    Shie-Liang Hsieh

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  1. Ming-Ting Huang
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Correspondence to Shie-Liang Hsieh.

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Huang, MT., Chen, ST., Wu, HY. et al. DcR3 suppresses influenza virus-induced macrophage activation and attenuates pulmonary inflammation and lethality. J Mol Med 93, 1131–1143 (2015). https://doi.org/10.1007/s00109-015-1291-1

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  • DOI: https://doi.org/10.1007/s00109-015-1291-1

Keywords

  • Decoy receptor 3
  • Influenza virus
  • M2 macrophage
  • Phosphoproteome