Crosstalk between the autonomic nervous system and the immune system by means of the sympathetic and parasympathetic pathways is a critical process in host defence. Activation of the sympathetic nervous system results in the release of catecholamines as well as neuropeptide Y (NPY). Here, we investigated whether phagocytes are capable of the de novo production of NPY, as has been described for catecholamines. We show that the synthesis of NPY and its Y1 receptor (Y1R) is increased in phagocytes in lungs following severe influenza virus infection. The genetic deletion of Npy or Y1r specifically in phagocytes greatly improves the pathology of severe influenza virus infection, which is characterized by excessive virus replication and pulmonary inflammation. Mechanistically, it is the induction of suppressor of cytokine signalling 3 (SOCS3) via NPY–Y1R activation that is responsible for impaired antiviral response and promoting pro-inflammatory cytokine production, thereby enhancing the pathology of influenza virus infection. Thus, direct regulation of the NPY–Y1R–SOCS3 pathway on phagocytes may act as a fine-tuner of an innate immune response to virus infection, which could be a therapeutic target for lethal influenza virus infection.

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Data availability

Nucleotide sequencing data that support the findings of this study have been deposited in Sequenced Read Archive in the DNA Data Bank of Japan (DDBJ) and are available under the accession number DRA007253. The data that support the findings of this study are available from the corresponding author upon request.

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The authors thank all members of their laboratories for helpful discussions. Y.Imai is supported by JSPS KAKENHI (S) grants 17H06179, 17K19693 and 15H05978. M.O. is supported by JSPS KAKENHI grant 17H06302. A.Y. is supported by JSPS KAKENHI grants 17H06175 and 18H05376, and AMED-CREST grants 18gm1110009 and 18gm0510019. K.K. is supported by JSPS KAKENHI grants 30733422, 16K19013, 17H04028 and JST PRESTO grant JPMJPR13MD. H.O. is supported by the Core Research for Evolutional Science and Technology (JPMJCR14W3-CREST). Y.Imai is supported by the Takeda Science Foundation and the Uehara Memorial Foundation. The authors acknowledge the NGS core facility of the Genome Information Research Center at the Research Institute for Microbial Diseases of Osaka University for their support with RNA-seq.

Author information

Author notes

  1. These authors contributed equally: Seiki Fujiwara, Midori Hoshizaki.


  1. Laboratory of Regulation for Intractable Infectious Diseases, Center for Vaccine and Adjuvant Research (CVAR), National Institutes of Biomedical Innovation Health and Nutrition (NIBIOHN), Osaka, Japan

    • Seiki Fujiwara
    • , Midori Hoshizaki
    • , Yu Ichida
    • , Hiroyuki Takao
    • , Masahiro Gandou
    • , Hirotaka Imai
    • , Ryujiro Hara
    •  & Yumiko Imai
  2. Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany

    • Dennis Lex
    •  & Stefan Uhlig
  3. Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research (CVAR), National Institutes of Biomedical Innovation Health and Nutrition (NIBIOHN), Osaka, Japan

    • Etsushi Kuroda
    •  & Ken J. Ishii
  4. Laboratory of Vaccine Science, World Premier International Immunology Frontier Research Center, Osaka, Japan

    • Etsushi Kuroda
    •  & Ken J. Ishii
  5. Laboratory of Cell Systems, Institute for Protein Research, Osaka University, Osaka, Japan

    • Shigeyuki Magi
    •  & Mariko Okada
  6. Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan

    • Mariko Okada
  7. Neuroscience Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    • Herbert Herzog
  8. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

    • Akihiko Yoshimura
  9. Laboratory of Molecular Brain Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    • Hitoshi Okamura
  10. Institute of Molecular Biotechnology in the Austrian Academy of Sciences, Vienna, Austria

    • Josef M. Penninger
  11. Life Science Institute, University of British Columbia, Vancouver, Canada

    • Josef M. Penninger
  12. Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada

    • Arthur S. Slutsky
  13. Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada

    • Arthur S. Slutsky
  14. Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, Akita, Japan

    • Keiji Kuba
  15. Laboratory of Infection Systems, Institute for Protein Research, Osaka University, Osaka, Japan

    • Yumiko Imai


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K.K., S.U., A.S.S., J.M.P., A.Y., H.O., H.H. and Y.Imai conceived the study and designed the experiments. S.F., M.H., Y.Ichida, D.L., E.K., K.J.I., H.T., M.G., H.I., R.H. and H.O. performed the experiments. S.M., M.O. Y.Ichida, and Y.Imai analysed the data. Y.Imai and H.H. wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Yumiko Imai.

Supplementary information

  1. Supplementary Information

    Supplementary Figures 1–4 and uncropped data for blots and gels.

  2. Reporting Summary

  3. Supplementary Table 1

    This table contains a list of antibodies used in the study.

  4. Supplementary Table 2

    This table contains a list of sequences of qPCR primers used in the study.

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