Abstract

Lung-innervating nociceptor sensory neurons detect noxious or harmful stimuli and consequently protect organisms by mediating coughing, pain, and bronchoconstriction. However, the role of sensory neurons in pulmonary host defense is unclear. Here, we found that TRPV1+ nociceptors suppressed protective immunity against lethal Staphylococcus aureus pneumonia. Targeted TRPV1+-neuron ablation increased survival, cytokine induction, and lung bacterial clearance. Nociceptors suppressed the recruitment and surveillance of neutrophils, and altered lung γδ T cell numbers, which are necessary for immunity. Vagal ganglia TRPV1+ afferents mediated immunosuppression through release of the neuropeptide calcitonin gene–related peptide (CGRP). Targeting neuroimmunological signaling may be an effective approach to treat lung infections and bacterial pneumonia.

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Acknowledgements

We thank K. Blake and N. Lai for technical assistance, and J. Bubeck Wardenburg and C. Altier for helpful discussions. We thank M. Hoon (NIH) for Trpv1-Dtr mice, C. Benoist (Harvard Medical School) and A. Mann (Harvard Medical School) for Tcrd−/− mice, G. Pier (Brigham and Women's Hospital) and M. Gadjeva (Brigham and Women's Hospital) for P. aeruginosa, R. Malley (Boston Children's Hospital) for S. pneumoniae, and M. Otto (NIH) for S. aureus bacterial strains. This work was supported by National Institutes of Health (NIH) grants DP2AT009499 (I.M.C.), K22AI114810 (I.M.C.), R01AI130019 (I.M.C.), 1KO8AI123516 (P.R.B.), and R01HL132255 (S.D.L.); an HHMI Faculty Scholars Award (S.D.L.); NIH 5F31HL132645 (B.D.U.); and Canadian Institutes of Health Research (CIHR) grant RS-342013 (B.G.Y.).

Author information

Affiliations

  1. Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts, USA.

    • Pankaj Baral
    • , Meghna Bist
    • , Talia Kirschbaum
    • , Yibing Wei
    • , Yan Zhou
    •  & Isaac M Chiu
  2. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.

    • Benjamin D Umans
    •  & Stephen D Liberles
  3. Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

    • Lu Li
    •  & Bryan G Yipp
  4. Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Antonia Wallrapp
    •  & Vijay K Kuchroo
  5. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Patrick R Burkett

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Contributions

P.B. and I.M.C. conceived the study. P.B., B.D.U., L.L., B.G.Y., A.W., P.R.B., V.K.K., S.D.L., and I.M.C. designed experiments, analyzed data, and interpreted results. P.B. performed animal infections, survival analysis, bacterial-load recovery, cytokine measurements, FACS, CGRP assays, and neutrophil killing experiments; B.D.U. performed VG injections and immunostaining; A.W. and P.R.B. performed purification of lung cells and quantitative PCR experiments; M.B. performed lung immunostaining and quantification; T.K. and Y.W. performed cytokine measurements and histology; Y.Z. performed neuronal cultures and CGRP assays; L.L. and B.G.Y. performed animal infections with in vivo intravital microscopy of neutrophil movement and migration. P.B. and I.M.C. wrote the manuscript, which was edited by S.D.L., B.G.Y., B.D.U., P.B. and I.M.C.

Competing interests

P.B. and I.M.C. are co-inventors on a patent application filed by Harvard incorporating discoveries described in the manuscript.

Corresponding author

Correspondence to Isaac M Chiu.

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Videos

  1. 1.

    Neutrophil dynamic behaviors revealed using pulmonary intravital microscopy

    Mice were pretreated with either vehicle control or RTX 4 weeks prior to GFP-S. aureus (green) pneumonia. Animals received 1x108 CFU into the lung and intravital imaging was performed at 4 hours post-infection. Neutrophils were visualized using fluorescently conjugated anti-Ly6G antibodies (red) and the endothelium was visualized using fluorescently conjugated anti-CD31 antibodies given intravenously prior to imaging. Representative video recordings of experiments from vehicle control and RTX-treated mice are shown side by side for comparison and then individually. Imaging experiments were repeated 3 separate times for vehicle control and 4 times for RTX.

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DOI

https://doi.org/10.1038/nm.4501