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


CONCLUSIONS
• 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.
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
Ming-Ting
MT
Huang
Department of Microbiology and Immunology, School of Medicine, Taipei Medical University, Taipei, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Szu-Ting
ST
Chen
Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
Hsin-Yi
HY
Wu
Institute of Chemistry, Academia Sinica, Taipei, Taiwan.|Genomics Research Center, Academia Sinica, 128, Academia Road, Sec. 2, Nankang District, Taipei, 115, Taiwan.
Yu-Ju
YJ
Chen
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Teh-Ying
TY
Chou
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan. slhsieh@gate.sinica.edu.tw.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. slhsieh@gate.sinica.edu.tw.|Genomics Research Center, Academia Sinica, 128, Academia Road, Sec. 2, Nankang District, Taipei, 115, Taiwan. slhsieh@gate.sinica.edu.tw.|Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan. slhsieh@gate.sinica.edu.tw.|Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan. slhsieh@gate.sinica.edu.tw.
Shie-Liang
SL
Hsieh
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D009980:Influenza A virus; D008168:Lung / Q000821:virology; D008262:Macrophage Activation / Q000276:immunology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D011014:Pneumonia / Q000276:immunology*; D017434:Protein Structure, Tertiary; D053323:Receptors, Tumor Necrosis Factor, Member 6b / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000276:immunology
D016207:Cytokines; D019812:Heparan Sulfate Proteoglycans; D007074:Immunoglobulin G; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D011993:Recombinant Fusion Proteins; D051193:Toll-Like Receptors; D020928:Mitogen-Activated Protein Kinases
Decoy receptor 3; Influenza virus; M2 macrophage; Phosphoproteome