caa a22 4500 605543496 CHVBK 20210128100926.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s00109-015-1291-1 doi (NATIONALLICENCE)springer-10.1007/s00109-015-1291-1 DcR3 suppresses influenza virus-induced macrophage activation and attenuates pulmonary inflammation and lethality [Elektronische Daten] [Ming-Ting Huang, Szu-Ting Chen, Hsin-Yi Wu, Yu-Ju Chen, Teh-Ying Chou, Shie-Liang Hsieh] 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. Springer-Verlag Berlin Heidelberg, 2015 Decoy receptor 3 nationallicence Influenza virus nationallicence M2 macrophage nationallicence Phosphoproteome nationallicence Huang Ming-Ting Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan aut Chen Szu-Ting Department of Microbiology and Immunology, School of Medicine, Taipei Medical University, Taipei, Taiwan aut Wu Hsin-Yi Institute of Chemistry, Academia Sinica, Taipei, Taiwan aut Chen Yu-Ju Institute of Chemistry, Academia Sinica, Taipei, Taiwan aut Chou Teh-Ying Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan aut Hsieh Shie-Liang Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan aut Journal of Molecular Medicine Springer Berlin Heidelberg 93/10(2015-10-01), 1131-1143 0946-2716 93:10<1131 2015 93 109 https://doi.org/10.1007/s00109-015-1291-1 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00109-015-1291-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Huang Ming-Ting Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan aut NATIONALLICENCE 700 1- Chen Szu-Ting Department of Microbiology and Immunology, School of Medicine, Taipei Medical University, Taipei, Taiwan aut NATIONALLICENCE 700 1- Wu Hsin-Yi Institute of Chemistry, Academia Sinica, Taipei, Taiwan aut NATIONALLICENCE 700 1- Chen Yu-Ju Institute of Chemistry, Academia Sinica, Taipei, Taiwan aut NATIONALLICENCE 700 1- Chou Teh-Ying Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan aut NATIONALLICENCE 700 1- Hsieh Shie-Liang Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan aut NATIONALLICENCE 773 0- Journal of Molecular Medicine Springer Berlin Heidelberg 93/10(2015-10-01), 1131-1143 0946-2716 93:10<1131 2015 93 109