Pulmonary phagocyte-derived NPY controls the pathology of severe influenza virus infection

Abstract

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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Fig. 1: NPY is synthesized in excess in pulmonary phagocytes in severe influenza in mice.
Fig. 2: Deletion of NPY improves the pathology of severe influenza virus infection.
Fig. 3: Phagocyte-specific NPY Y1R deletion improves the pathology of severe influenza virus infection.
Fig. 4: SOCS3 is involved in the NPY–Y1-mediated pathology of severe influenza virus infection.
Fig. 5: The NPY–Y1R–SOCS3 axis on phagocytes enhances pulmonary inflammation in parallel to virus replication in influenza virus infection.

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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Acknowledgements

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.

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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.

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Correspondence to Yumiko Imai.

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

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Supplementary Table 1

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

Supplementary Table 2

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

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Fujiwara, S., Hoshizaki, M., Ichida, Y. et al. Pulmonary phagocyte-derived NPY controls the pathology of severe influenza virus infection. Nat Microbiol 4, 258–268 (2019). https://doi.org/10.1038/s41564-018-0289-1

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