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

Ming Ting Huang, Szu Ting Chen, Hsin Yi Wu, Yu Ju Chen, Teh Ying Chou, Shie Liang Hsieh

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1131-1143
Number of pages13
JournalJournal of Molecular Medicine
Volume93
Issue number10
DOIs
Publication statusPublished - May 5 2015

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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